Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
I think that several of us in medicinal chemistry have been keeping our eyes out for a chance to work in a pentafluorosulfanyl (SF5) group. I know I have - I actually have a good-sized folder on the things, and some of the intermediates as well, but I've never found the right opportunity. Yeah, I know, they're big and greasy, but since when that that ever stop anyone in this business?
Well, here are are some new routes to (pentafluorosulfanyl)difluoroacetic acid, a compound that had previously only existed in a few scattered literature reports (and those from nasty chemistry). So we all have even less of an excuse to start polluting enhancing our screening collections with these things. Who's first?
The thesis is miserable. One and a half years of new substances prepared like baker’s bread rolls… and in addition, lots of negative results just where I was looking for significant results, and further, results that I cannot even publish because I fear that a competent chemist will find them and prove to me that the camel is missing its humps. One learns to be modest.
Now, Haber was definitely someone to take seriously. He's showing up in "The Chemistry Book", for sure, both for his historic ammonia process and his work in chemical warfare. He was a good enough chemist to know that his doctoral work was not all that great, although he seems to have followed my own recommended path to get that degree as soon as is consistent with honor and not making enemies.
The post's author, MB, wonders what this says about organic synthesis in general. How much of it is just baking bread rolls, and how bad is that? My own take is that the sort of think that Haber was regretting is the lowest form of synthesis. We've all seen the sorts of papers - here is a heterocyclic core, of no particular interest that anyone has ever been able to show. Here it has an amine. Here are twenty-five amides of that amine. Here is our paper telling you about them. Part fourteen in a series. In six months, the sulfonamides. This sort of things gets published, when it does, in the lowest tiers of the journals, and rightly so. There's nothing wrong with it (well, not usually, although this stuff isn't always the most careful work in the world). But there's nothing right with it either. It's reference data. Someone, someday, might stumble into this area of chemical space again, and when they do, they'll find a name scratched onto the wall and below it, a yellowing pile of old spectral data.
I've wondered before about what to do with those sorts of papers. There are so many compounds in the world of organic chemistry that the marginal utility of describing new random ones, while clearly not zero, is very, very close to it, especially if they're not directed towards any known use other than to make a manuscript. So if this is what's meant by baking rolls, then it's not too useful.
But I'm a medicinal chemist. When I start working on a new hit structure, I will most likely turn around and put the biggest pan of bread rolls into the biggest oven I can find. This, though, is chemistry with a purpose - there's some activity that I'm seeking, and if cranking out compounds is the best and/or fastest way to move in on it, then crank away. I'm not going to turn that blast of analogs into a paper; most (maybe all) of them will be tested, found wanting, and make their way into our compound archives. Their marginal utility is pretty low, too, given the numbers of compounds already in there, but it's still by far the best thing to do with them. Any that show activity, though, will get more attention.
I really don't mind that aspect of the synthesis I do. Setting up a row of easy reactions is actually kind of pleasant, because I know that (1) they're likely to work, and (2) they're going to tell me something I really want to know after I send them off for testing. Maybe they aren't bread rolls after all - they're bricks, and I can just possibly build something from them.
Here's a look at the life of a process/scale-up chemist while trying to get a key reaction to fly right. This is just the sort of problem these people deal with all the time - time pressure, troublesome reagent sourcing, purity and workup problems. And there's no place to hide, because you're always working on compounds that everyone cares about. (This story has a happy ending, but those are not guaranteed!)
I wanted to note my latest column for the RSC's Chemistry World, because I thought many readers here would be able to relate to it. I have a series of proposals for running the worst drug discovery organization I can think of - a set of simple rules that I think would bring things to a frantic, juddering halt while seeming to aim at enhancing everyone's productivity. A sample:
Appearances matter. And if it comes to a contest between surface and substance, then the glossiest surface wins. Woe to anyone whose presentations are not smooth and slick, with as many colorful charts as possible. Woe, similarly, to those who fail to tell anyone who asks (and many who don’t) how cleanly and tightly their current project is running. The first step to making problems disappear is to get them out of everyone’s sight. Right?
There will be many, many meetings to show off those beautiful slides. Multiple overlapping layers of meetings: it’s the only way to keep things running smoothly. Your worth as a manager, and as a human being, is tied to how many people you can cause to assemble in a room on a regular basis and how frequently you can get them to stand up in front of you.
I'm coming up (this fall) on twenty-five years of industrial research, and I found this column alarmingly easy to write. I was reminded of C. S. Lewis' experience in composing The Screwtape Letters, and his reluctance to write any more in that style. It really does just come out like opening up a water line once you get started, which says something about human nature.
Since I'm in the process of moving my office, I've been taking time to do something that's needed to be done for quite a while: cleaning out my files. Somewhere around 2007 or so, I made the switchover to keeping PDFs as my primary filing system, with paper copies when needed. There was a transitional period, which I ended up splicing together by checking through my recent printed copies and backfilling those into my digital archive, but after that, it was all digital. (For the record, I'm still using Zotero for that purpose, although there are several equally valid alternatives, both commercial and freeware).
But I still had a pretty massive filing cabinet full of stuff, and I let that remain undisturbed, even though I knew some of it was surely junk. Only when I started digging into it did I realize just how much of it was little more than that. I'd estimate that I've thrown at least 80% of my files into the recycling bin, an act that would have made me uneasy only a few years ago, and horrified me in, say, 2004. It was easier than I thought, though.
That's because the folders easily fell into several broad categories. In the medical/biological sections of the cabinet, there were "Topics I'm Unlikely to Revisit - And When I Do, It Won't Be With These References". Those went right into the recycling bin. And there were "Topics I May Well Revisit, But When I Do, It Won't Be With These References". Those, after a glance through their contents, went into the bin as well. These were folders on (for example) disease areas that I've worked on in the past, and might conceivably work on again, but a folder full of ten-year-old biomedical articles is not that useful compared to the space it takes up and the trouble it takes to move it. And if that sounds borderline to you, how about the ones that hadn't been updated since the late 1990s? Junk. Nothing in the literature goes out of date faster than a state-of-current-disease-research article.
Moving to the chemistry folders, I was quickly surprised at how many of those I was throwing away as well. The great majority of the printed papers I kept were chemistry ones, but the great majority of what I started out with went into the recycling bin anyway. Digging through them was, in many cases, a reminder of what keeping up with the literature used to be like, back in the day. It was a time when if you found a useful-looking paper, you copied it out and put it in your files, because there was no telling when or if you'd be able to find it again. If you were one of the supremely organized ones, you drew a key reaction or two on an index card and filed that according to some system of your own devising - that's before my time, but I saw people doing that back when I was a grad student. The same sort of pack-ratting persisted well into the 1990s, though, but eroded in the face of better access to Chemical Abstracts (and the rise of competing databases). Finding that reaction, or others like it, or even better references than the ones you knew about, became less and less of a big deal.
So in my files, over in the section for "Synthesis of Amines", there was a folder on the opening of epoxides by amines. And in it were several papers I'd copied in the late 1980s. And some printed-out hits from SciFinder searches in about 1993. And a couple of reactions that I'd seen at conferences, and a paper from 1997 showing how you could change the site of ring opening, sometimes, with some systems. Into the bin it went, despite the feeling (not an inaccurate one) that I was throwing away work that I'd put into assembling all that. But if I find myself wanting to run such a reaction, I can probably set something up that'll work fairly well, and if it doesn't, I can probably find a review article (or two) where someone else has assembled the previous literature.
One of the biggest problems with my chemistry files, I realized, was the difficulty of searching them. I'd gotten used to the world of SciFinder and Reaxsys and Google and PubMed, where information can be called up any way you like. File folders, though, do not speak of their contents. Unless you have the main points of that content committed to memory, you have to open them up and flip through them, hoping for something relevant to pop up. I can well remember doing that in the early 1990s with some of these very folders ("Hmm, let's see what methods I have for such-and-such"), but that style of searching disappeared many years ago. You can now see what methods everyone has, and quickly find out what's been added to the pile since the last time you looked. Younger researchers who've grown up in that world may find it odd that I'm pointing out that water is wet, but my earliest file-cabinet folders were started in another time. File folders are based on tagging (and in its purest form, a physical label), and I agree with people who say that the ability to search is more important and useful than the ability to tag.
So, what did I keep? Folders on specialized topics that I recalled were very difficult to assemble, in a few cases. Papers that I know that I've referred to several times over the years. Papers that refer directly to things that I'm currently working on. Some stuff that's so old that it falls under the category of memorabilia. And finally, papers on more current topics that I want to make sure that I also have in digital form, but didn't have time to check just now. But that three-inch-thick collection of nuclear receptor papers from 2000-2002? The papers on iron dienyl reagents that I copied off during a look at that chemistry in 1991, and never had a need to refer to after about ten days? A folder of reductive amination conditions from the late 1980s? Into the big blue bin with all of it.
It's clear that many readers here are not fans of open-office designs - and whether that percentage is higher or lower among chemists (or scientists in general) is an interesting question that hasn't been settled yet. But if you're one of those dissenters, take heart: this New Yorker piece is the herald of the backlash.
In 2011, the organizational psychologist Matthew Davis reviewed more than a hundred studies about office environments. He found that, though open offices often fostered a symbolic sense of organizational mission, making employees feel like part of a more laid-back, innovative enterprise, they were damaging to the workers’ attention spans, productivity, creative thinking, and satisfaction. Compared with standard offices, employees experienced more uncontrolled interactions, higher levels of stress, and lower levels of concentration and motivation. . .
There are plenty more links of the same type in the post, so if you're looking for ammunition against open-office plans, that's your one-stop superstore. Designers of new spaces in this industry sure do seem to love 'em, though. But personally, I'm not enthusiastic. I like talking to people about ideas, and I like hearing what other people are up to. But when I'm thinking, I shut the door. When I'm interrupted, my thoughts take off like the pigeons do when someone rides their VestaVespa into the market square in an old Italian movie. Update: my brain was apparently thinking about the asteroid instead of the scooter). It's almost physically painful to feel the structure I was building collapse, knowing that I'm going to have to assemble it all again.
I enjoyed this take on med-chem, and I think he's right:
There are a large set of "don't do this". When they predict failure, you usually shouldn't go there as these rules are moderately reliable.
There is an equally large set of "when you encounter this situation, try this" rules. Their positive predictive power is very very low.
Even the negative rule, the what-to-avoid category, aren't as hard as fast as one would like. There are some pretty unlikely-looking drugs out there (fosfomycin, nitroglycerine, suramin, and see that link above for more). These structures aren't telling you to go out and immediately start imitating them, but what they are telling you is that things that you'd throw away can work.
But those rules are still right more often than the "Here's what to do when . . ." ones, as John Alan Tucker is saying. Every experienced medicinal chemist has a head full of these things - reduce basicity to get out of hERG problems, change the logP for blood-brain-barrier penetration, substitute next to a phenol to slow glucuronidation, switch tetrazole/COOH, make a prodrug, change the salt, and on and on. These work, sometimes, but you have to try them every time before moving on to anything more exotic.
And it's the not-always-right nature of the negative rules, coupled with the not-completely-useless nature of the positive ones, that gives everyone room to argue. Someone has always tried XYZ that worked, while someone else has always tried XYZ when it didn't do a thing. Pretty much any time you try to lay down the law about structures that should or shouldn't be made, you can find arguments on the other side. The rule-of-five type guidelines look rather weak when you think about all the exceptions to them, but they look pretty strong when you compare them to all the other rules that people have tried, and so on.
In the end, all we can do is narrow our options down from an impossible number to a highly improbable number. When (or if) we can do better, medicinal chemistry will change a great deal, but until then. . .
I've had the chance to use good old elemental bromine this morning, for the first time in several years. I can never see the stuff without thinking of this incident, a memorable part of the first synthetic scheme I ever tried that involved bromine. In the same way, every time I come across thiophenol - which isn't often, fortunately - I'm immediately taken back to this chemistry, which is a reaction I'll never forget either, despite numerous attempts to expunge it from my memory.
So here's a good question for a Monday: what reagents immediately recall something from your chemical past, and why? I'd assume that most working organic chemists have a few of these in their past. The common reagents all tend to blur together, but there will always be a few that have shown up only in one or two memorable instances. So what are yours?
So the picture that's emerging of Merck's drug discovery business after this round of cuts is confused, but some general trends seem to be present. West Point appears to have been very severely affected, with a large number of chemists shown the door, and reports tend to agree that bench chemists were disproportionately hit. The remaining department would seem to be top-heavy with managers.
Top-heavy, that is, unless the idea is that they're all going to be telling cheaper folks overseas what to make, that is. So is Merck going over to the Pfizer-style model? I regard this as unproven on this scale. In fact, I have an even lower opinion of it than that, but I'm sure that my distaste for the idea is affecting my perceptions, so I have to adjust accordingly. (Not everything you dislike is incorrect, just as not every person that's annoying is wrong).
But it's worth realizing that this is a very old idea. It's Taylorism, after Frederick Taylor, whose thinking was very influential in business circles about 100 years ago. (That Wikipedia article is written in a rather opinionated style, which the site has flagged, but it's a very interesting read and I recommend it). One of Taylor's themes was division of labor between the people thinking about the job and the people doing it, and a clearer statement of what Pfizer (and now Merck) are trying to do is hard to come by.
The problem is, we are not engaged in the kind of work that Taylorism and its descendants have been most successfully applied to. That, of course, is assembly line work, or any work flow that consists of defined, optimizable processes. R&D has proven. . .resistant to such thinking, to put it mildly. It's easy to convince yourself that drug discovery consists of and should be broken up into discrete assembly-line units, but somehow the cranks don't turn very smoothly when such systems are built. Bits and pieces of the process can be smoothed out and improved, but the whole thing still seems tangled, somehow.
In fact, if I can use an analogy from the post I put up earlier this morning, it reminds me of the onset of turbulence from a regime of laminar flow. If you model the kinds of work being done in some sort of hand-waving complexity space, up to a point, things run smoothly and go where they're supposed to. But as you start to add in key steps where the driving forces, the real engines of progress, are things that have to be invented afresh each time and are not well understood to start with, then you enter turbulence. The workflow become messy and unpredictable. If your Reynolds numbers are too high, no amount of polish and smoothing will stop you from seeing turbulent flow. If your industrial output depends too much on serendipity, on empiricism, and on mechanisms that are poorly understood, then no amount of managerial smoothing will make things predictable.
This, I think, is my biggest problem with the "Outsource the grunt work and leave the planning to the higher-ups" idea. It assumes that things work more smoothly than they really do in this business. I'm also reminded a bit of the Chilean "Project Cybersyn", which was to be a sort of control room where wise planners could direct the entire country's economy. One of the smaller reasons to regret the 1973 coup against Allende is that the chance was missed to watch this system bang up against reality. And I wonder what will happen as this latest drug discovery scheme runs into it, too.
Update: a Merck employee says in the comments that there hasn't been talk of more outsourcing, If that proves to be the case, then just apply the above comments to Pfizer.
This is not one of the most pressing topics in the world, but it's certainly on my mind right now. I'm in the process of weighing out a number of acetophenones (literally - the balance is waiting for me over to my right). And I have to tell you, 2-acetylpyridine really smells like corn chips. I think several others in this group also have some of that character, but they're overwhelmed by the sheer tortillachipivity of the 2-acetylpyridine. Now I want a bowl of salsa, and it's only ten o'clock in the morning.
So, fellow organic chemists: what reagents remind you of food? We've talked about things that smell awful around here. How about things that actually smell appealing, for once? Nominations in the comments. . .
Update: by gosh, my nose is not leading me astray. 2-acetylpyridine is indeed found in tortilla chips.
Second update: in further news, I can now report that 3,4-dimethoxyacetophenone smells rather like a freshly opened package of bacon. Science sure is marching along this morning.
Third update: to judge from the color of the subsequent reaction, which might now be described as "spicy Szechuan motor oil", were there such a thing, I'd be willing to bet that it doesn't smell very much like tortilla chips any more. I will not, I think, be reporting back on what it does smell like.
Here's a paper from the Carreira group at the ETH, in collaboration with Roche, that falls into a category I've always enjoyed. I put these under the heading of "Synthetic routes into cute functionalized ring systems", and you can see my drug-discovery bias showing clearly.
Med-chem people like these kinds of molecules. (I have a few of them drawn here, but all the obvious variations are in the paper, too). They aren't in all the catalogs (yet), they're in no one's screening collection, and they have a particular kind of shape that might not be covered by anything else we already have in our files. There's no reason why something like this might not be the core of a bunch of useful compounds - small saturated nitrogen heterocycles fused to other rings sure do show up all over the place.
And the purpose of this sort of paper matches a drug discovery person's worldview exactly: here's a reasonable way into a large number of good-looking compounds that no one's ever screened, so go to it. (Here's an earlier paper from Carreira in the same area). The chemistry involved in making this things is good, solid stuff: it's not cutting-edge, but it doesn't have to be. It's done on a reasonable scale, and it certainly looks like it would work just fine. I can understand why readers from other branches of organic chemistry would skip over a paper like this. No theoretical concerns are addressed in the syntheses, no natural products are produced, no new catalysts are developed, and no new reactions are discovered. But new scaffolds are being made, and for a medicinal chemist, that's more than enough right there. This is chemistry that does just what it needs to do, quickly, and gets out of the way, and I wouldn't mind seeing a paper or two like this every time I open up my RSS feeds.
Steve Ballmer's departure from Microsoft, snidely remarked on here, has prompted any number of "What went wrong?" pieces to appear. One of the key documents, though, is from last year: Kurt Eichenwald's writeup in Vanity Fair. The editorial staff has helpfully illustrated it with a photo of Ballmer himself that's so characteristic of his style that it's liable to give ex-Microsofters the shivering flashbacks.
One of the common themes to all these articles is the company's use of "stack ranking", where you evaluate your direct reports and rank them top to bottom. The bottom performers get hammered, no matter how they might have done on some hypothetical absolute scale. If you happen to have a great group of high-performing people working for you - too bad. Some of them are going to be ranked at the imaginary bottom, and get punished for it. Here's Eichenwald:
At the center of the cultural problems was a management system called “stack ranking.” Every current and former Microsoft employee I interviewed—every one—cited stack ranking as the most destructive process inside of Microsoft, something that drove out untold numbers of employees. The system—also referred to as “the performance model,” “the bell curve,” or just “the employee review”—has, with certain variations over the years, worked like this: every unit was forced to declare a certain percentage of employees as top performers, then good performers, then average, then below average, then poor.
“If you were on a team of 10 people, you walked in the first day knowing that, no matter how good everyone was, two people were going to get a great review, seven were going to get mediocre reviews, and one was going to get a terrible review,” said a former software developer. “It leads to employees focusing on competing with each other rather than competing with other companies.”
. . .For that reason, executives said, a lot of Microsoft superstars did everything they could to avoid working alongside other top-notch developers, out of fear that they would be hurt in the rankings. And the reviews had real-world consequences: those at the top received bonuses and promotions; those at the bottom usually received no cash or were shown the door.
You can well imagine the sorts of behaviors this system promotes. A Microsoft engineer said in the article that "One of the most valuable things I learned was to give the appearance of being courteous while withholding just enough information from colleagues to ensure they didn’t get ahead of me on the rankings". What's even more dysfunctional about this system is that it was not officially acknowledged by the managers. Here's a former Microsoft employee writing in Slate:
Then I had to explain things to my reports. This illustrated another problem with the system: It destroyed trust between individual contributors and management, because the stack rank required that all lower-level managers systematically lie to their reports. Why? Because for years Microsoft did not admit the existence of the stack rank to nonmanagers. Knowledge of the process gradually leaked out, becoming a recurrent complaint on the much-loathed (by Microsoft) Mini-Microsoft blog, where a high-up Microsoft manager bitterly complained about organizational dysfunction and was joined in by a chorus of hundreds of employees. The stack rank finally made it into a Vanity Fair article in 2012, but for many years it was not common knowledge, inside or outside Microsoft. It was presented to the individual contributors as a system of objective assessment of “core competencies,” with each person being judged in isolation.
Why do I bring this up? Because many large drug companies persist in ranking-and-rating behaviors that are very nearly as stupid, and very nearly as destructive. And we've been doing it for years. At any rate, I've been complaining about it for years, and I'm certainly not alone. Rating people in research is notoriously difficult already, but rating them by jamming them into an artificial (and mathematically illiterate) template is even worse. If you want people to focus on stepping over each other, pit them against each other with a good, hard stack ranking system. If you'd like them to do something else with their time, you might want to rethink.
Andre the Chemist is talking Lab Instrument Nostalgia at his blog. I know what he means, but mostly, when I think of old equipment, I'm just glad that I'm not using it any more. I remember, for example, the JEOL NMR machines with the blue screen and light pen, and a water-cooled 80MHZ NMR made by IBM, of all people. But if I saw either of them today, I would react with a sort of interested horror.
Update: a little searching around brought me this picture of the IBM machine. Check out the cool 1980 tech!
Here's a new development in the office/lab architecture topic, which has been the subject of lively discussion around here over the years. Biogen Idec has been putting up a new building (I've been following its progress as I go past it), and they're getting ready to move in. According to the Boston Globe, the entire thing is a completely office-less and cubicle-less space.
Building 9 has no private offices, just individually designed workstations called “I spaces” and common “huddle rooms” for private phone calls or spontaneous meetings. Each floor has two “walk stations” where employees can work while walking on treadmills. The company has scrapped telephone landlines for Building 9 employees, who are issued laptops and headsets.
“This whole idea of no offices is a little controversial,” admitted chief executive George Scangos. “It’s a new way of working. The idea is to foster more collaboration. People can talk to each other now. A lot of ideas can come out of these informal discussions.”
. . .But will some Biogen Idec recruits be pining for their own private offices?
“There may be some people who say, ‘I don’t want this, I want an office,’ ” Scangos acknowledged. After pausing, he said quietly, “Then they don’t come here.”
Problem is, like all other big-culture-change ideas, it takes years before you find out if it's working or not. But Biogen seems to be very big on the idea, and it'll be quite interesting to hear reports about how it's working (or not).
Thanks to Lisa Jarvis at C&E News for the tip, via Twitter.
I was running some good old brute force reactions in the lab the other day, the kind with rock-solid reactants and products. The way to get such reactions to go, if they're a bit slow on you, is of course to heat them up. One of my Laws of the Lab, formulated back in grad school, was "A slow reaction at room temperature is Nature's way of telling you to reflux that sucker".
That's not always true - there are reactants that won't put it with that sort of treatment and find something else to do, just as there are products that are unstable to the heat that might have been used to make them. (That last situation is a natural for flow chemistry, by the way, where you might be able to get the products out of the hot zone before they have a chance to do something else). But for the things I was doing, and for many other kinds of reactions, a good blast of heat can be just the thing.
The microwave reactor is a good way to put this into practice. Seal up your reaction in a vial and tell the thing to heat up the contents to, say, 120C for half an hour. Reaction done, or not? If not, then maybe another half hour - or maybe you should set one up where you hit it at 140C for a shorter time? Or 160? Why not? You might have a bunch of five- or ten-minute reactions ready to go, and you won't know until you crank on them a bit. You might also have a shortcut to a tube of blackened gorp, but how else do you find out that you've gone too far? The nice thing about the sealed microwave vials is that they can take a good amount of pressure. You can use "normal" solvents at higher temperature than you would ordinarily. My limit is acetonitrile at about 190C in a small vial, which is about triple its standard boiling point, and gives (in my case) a pressure of about 17 or 18 atmospheres in the tube.
Now, this can take some getting used to, for less experienced chemists. One of the things that is drummed into students in the lab is the Never Heat a Closed System, and there are clearly a lot of good reasons for caution. But sometimes heating a closed system is just the thing. There are several lab-scale gizmos to allow sealed-tube reactions to be run more safely, for just these Need For Heat reasons. Another nice thing about a sealed tube is that your reactants (and products) can't get away. Running stuff in decalin or sulfolane (classic high-boiling solvents) can put you in a situation where the reaction is merrily boiling away in the flask, but some of your own materials are fleeing up the condenser in terror, likely to whoof off and vanish out the fume hood exhaust if you keep it up.
I would be a lot more circumspect about such conditions if it weren't for the robustness of the commercial microwave platform. People run stuff like this all the time, so you can blast away with more confidence. Not that you can't blow one out, especially if there's an exothermic reaction waiting to take off on you. You'll want to sneak up on a new reaction to make sure that it's not waiting for you with one of those thermodynamic jack-in-the-boxes. And keep in mind that I'm a discovery chemist. A fifty-milligram reaction is fine by me. Proposing to the scale-up group, though, that they run a bunch of sealed acetonitrile reactions at 190C will get you a different reception. You can do that stuff on larger scale, though, if you're truly motivated. That's what those big solid metal reactors with the screwed-down tops are for, but that's also what pressure monitors, blast shields, and differential scanning calorimeters are for, too. Scale matters - it matters a lot, and a liter of hot acetonitrile (much less fifty liters) under high pressure is a very different thing than a couple of mLs in a thick-walled vial. The latter could easily be one of a dozen routine reactions queued up in a microwave rack, but the former could easily be your last sight on this earth, and you'd better plan accordingly.
Here's a neat bit of reaction optimization from the Aubé lab at Kansas. Update: left the link out before - sorry!) They're trying to make one of their workhorse reactions, the intramolecular Schmidt, a bit less nasty by cutting down on the amount of acid catalyst. The problem with that is product inhibition: the amide that's formed in the reaction tends to vacuum up any Lewis acid around, so you've typically had to use that reagent in excess, which is not a lot of fun on scale.
By varying a number of conditions, they've found a new catalyst/solvent system that's quite a bit friendlier. I keep meaning to try some of these reactions out (they make some interesting molecular frameworks), and maybe this is my entry into them. But the general problem here is one that every working organic chemist has faced: reactions that, for whatever reason, stop partway through. In this situation, there's at least a reasonably hypothesis why things grind out, and there's always been a less-than-elegant way around it (dump in more Lewis acid).
I'm sure, though, that everyone out there at the bench has had reactions that just. . .stop, for reasons unknown, and can't be pushed forward by addition of more anything. I've always wondered what's going on in those situations (probably a lot of things, from case to case), and they're always a reminder of just how little we sometimes really understand about what's going on inside our reaction flasks. Aggregates or other supramolecular complexes? Solubility problems? Adsorption onto heterogeneous reactants? Getting a handle on these things isn't easy, and most people don't bother doing it, unless they're full-out process chemists in industry.
Here's a question for the organic chemists in the crowd, and not just those in the drug industry, either. Over the last few years, though, there's been a lot of discussion about how drug company compound libraries have too many compounds with too many aromatic rings in them. Here are some examples of just the sort of thing I have in mind. As mentioned here recently, when you look at real day-to-day reactions from the drug labs, you sure do see an awful lot of metal-catalyzed couplings of aryl rings (and the rest of the time seems to be occupied with making amides to link more of them together).
Now, it's worth remembering that some of the studies on this sort of thing have been criticized for stacking the deck. But at the same time, it's undeniable that the proportion of "flat stuff" has been increasing over the years, to the point that several companies seem to be openly worried about the state of their screening collections.
So here's the question: if you're trying to break out of this, and go to more three-dimensional structures with more saturated rings, what are the best ways to do that? The Diels-Alder reaction has come up here as an example of the kind of transformation that doesn't get run so often in drug research, and it has to be noted that it provides you with instant 3-D character in the products. What we could really use are reactions that somehow annulate pyrrolidines or tetrahydropyrans onto other systems in one swoop, or reliably graft on spiro systems where there was a carbonyl, say.
I know that there are some reactions like these out there, but it would be worthwhile, I think, to hear what people think of when they think of making saturated heterocyclic ring systems. Forget the indoles, the quinolines, the pyrazines and the biphenyls: how do you break into the tetrahydropyrans, the homopiperazines, and the saturated 5,5 systems? Embrace the stereochemistry! (This impinges on the topic of natural-product-like scaffolds, too).
My own nomination, for what it's worth, is to use D-glucal as a starting material. If you hydrogenate that double bond, you now have a chiral tetrahydropyran triol, with differential reactivity, ready to be functionalized. Alternatively, you can go after that double bond to make new fused rings, without falling back into making sugars. My carbohydrate-based synthesis PhD work is showing here, but I'm not talking about embarking on a 27-step route to a natural product here (one of those per lifetime is enough, thanks). But I think the potential for library synthesis in this area is underappreciated.
A conversation the other day about 2-D NMR brought this thought to mind. What do you think are the most underused analytical methods in organic chemistry? Maybe I should qualify that, to the most underused (but potentially useful) ones.
I know, for example, that hardly anyone takes IR spectra any more. I've taken maybe one or two in the last ten years, and that was to confirm the presence of things like alkynes or azides, which show up immediately and oddly in the infrared. Otherwise, IR has just been overtaken by other methods for many of its application in organic chemistry, and it's no surprise that it's fallen off so much since its glory days. But I think that carbon-13 NMR is probably underused, as are a lot of 2D NMR techniques. Any other nominations?
Over at NextMove software, they have an analysis of what kinds of reactions are being run most often inside a large drug company. Using the company's electronic notebook database and their own software, they can get a real-world picture of what people spend their time on at the bench.
The number one reaction is Buchwald-Hartwig amination. And that seems reasonable to me; I sure see a lot of those being run myself. The number two reaction is reduction of nitro groups to amines, which surprises me a bit. There certainly are quite a few of those - the fellow just down the bench from me was cursing at one just the other day - but I wouldn't have pegged it as number two overall. Number three was the good old Williamson ether synthesis, and only then do we get to the reaction that I would have thought would beat out either of these, N-acylation. After that comes sulfonamide formation, and that one is also a bit of a surprise. Not that there aren't a lot of sulfonamides around, far from it, but I was under the impression that a lot of organizations gave the the semi-official fish-eye, due to higher-than-average rates of trouble (PK and so on) down the line.
My first thought was that there might have been some big and/or recent projects that skewed the numbers around a bit. These sorts of data sets are always going to be lumpy, in the same way that compound collections tend to be (and for the same reasons). The majority of compounds (and reactions) pile up when a great big series of active compounds comes along with Structure X made via Reaction Scheme Y. But that, in a way, is the point: different organizations might have a slightly different rank-ordering, but it seems a safe bet that the same eight or ten reactions would always make up most of the list. (My candidate for number 6, the next one down on the above list: Suzuki coupling).
There's also a pie chart of the general reaction types that are run most often. The biggest category is heteroatom alkylation and arylation, followed by acylation in general. By the time you've covered those two, you've got half the reactions in the database. Next up is C-C bond formations (there are those Suzukis, I'll bet) and reductions. (Interestingly. oxidations are much further down the list). That same trend was noted in an earlier analysis of this sort, and nitro-to-amine reactions were thought to be the main reason for it, as seems to be the case here. There's at least one more study of this sort that I'm aware of, and it came to similar conclusions.
One of the things that might occur to an academic chemist looking over these data is that none of these are exactly the most exciting reactions in the world. That's true, and that's the point. We don't want exciting chemistry, because "exciting" means that it has a significant chance of not working. Our reactions are dull as the proverbial ditchwater (and often about the same color), because the excitement of not knowing whether something is going to pan out or not is deferred a bit down the line. Just getting the primary assay data back on the compounds you just made is often an exercise in finger-crossing. Then waiting to see if your lead compound made it through two-week tox, now that's exciting. Or the first bit of Phase I PK data, when the drug candidate goes into a person's mouth for the first time. Or, even more, the initial Phase II numbers, when you find out if it might actually do something for somebody's who's sick. Now those have all the excitement that you could want, and often quite a bit more. With that sort of unavoidable background, the chemistry needs to be as steady and reliable as it can get.
I have affection for some reagents, and have taken a dislike to others. That might be seen as odd, because if there's anything that can't return your feelings, it's a chemical reagent. But after some years in the lab, you associate some compounds (and some reactions) with good events, and others with spectacularly bad ones, so it's a natural response.
Today, for example, I'm breaking out some potassium hexamethyldisilazide, known in the trade (for obvious reasons) as K-HMDS. I'm in need of a strong base, and this one has worked for me in a couple of tight spots over the years, which makes me very friendly towards it. The first of those was back in grad school. It was, in retrospect, one of the first times I ever figured out what was going wrong with a reaction from first principles. Knowledge being power and all that, I was then able to come up with a fix, switching my base away from the lithium reagents I'd been using to KHMDS. I can still remember looking at the TLC plate in disbelief, having suddenly seen the yield go from flat zero to over 90%. I'll always be loyal after an experience like that.
There are others. As I've mentioned, I'll always love copper sulfate, just because of its color and because it was one of the first chemical reagents I ever owned as a boy. There are a couple of carbohydrate derivatives (such as good ol' "diacetone glucose") that, unlike some of their cousins, always treated me well during my PhD work, and I'm happy to see them on the rare occasions I have use for them. And as usual with the human brain, there are certain chemical smells that I immediately associate, nostalgically, with old labs. I'm not even sure what some of these are, but they're immediately recognizable, and my first thought is "Now that's chemistry".
But there's a flip side. There are reagents that have done nothing but waste my time and chew up my starting materials, and it's hard for me to warm up to them after that. I'm not sure if anyone likes trimethyl phosphite - it has a smell that seems as if would work its way through a concrete block - but I spent too much time trying to use it (unsuccessfully) for a tricky way out of a problem back in grad school, and I now associate its odor with frustration. I can tell that it's not just that it has a bad odor in general - ethyl vinyl ether is nobody's cologne, either, but that one makes me think of the summer of 1984 and bunch of Claisen rearrangements I was running, and I don't mind that at all. Mercuric oxide is colorful, so you'd think I might like it, but aside from it being toxic, I had some painful experiences with it in some old desulfurization reactions, and it'll never recover with me. And the so-called "higher-order" cuprates, made with copper cyanide - I'm not sure if anyone uses those any more, but I swore years ago to never touch one of those evil things again, and I've stuck to that.
My lists aren't always that absolute. As mentioned here, I went through a period where I absolutely could not take tosyl chloride, but not having to work with kilos of the stuff has gradually allowed it to move back into what's at least neutral territory. For me, that reagent is like running into someone from your old school that you didn't always care for at the time, but with whom you now seem to have at least some common ground in which to share memories.
So my shelves are full of friends and enemies. And now I'm off to see if my old pal, KHMDS, can come through for me again!
I enjoyed this from postdoc JesstheChemist on Twitter: "Busted. Just caught someone (who doesn't work in my lab) going through my lab drawers." Now that's a real-life lab comment if I ever saw one. It's a constant feature in academic labs, where there's usually limited equipment of one sort of another. There's less of it in industry, where we're relatively equipment-rich, but it certainly doesn't go away.
Glassware gets rummaged through, whether for that one tiny Dean-Stark trap, a funny-sized ground-glass stopper, or something as petty as a clean 25 mL round bottom. Run out of that fancy multicolor pH paper? The guy next to you keeps it in the second drawer. One-mL syringes ran out, and you need to dispense something right now? Third drawer.
I've seen people borrow things while they're in use. In grad school, I once had a short-path vacuum distillation going, with the receiving flasks cooled in a bath supported by a lab jack. I left for a few minutes while things were warming up, only to find my lab jack pilfered and replaced by a ragged stack of cork rings, which was not what I had in mind. Peeved, I hunted through the labs until I found the jack in the hood of a post-doc who was running something of his own. "I didn't think you were using it", was his response, which prompted me to ask what it looked like when I was actually using it.
Then you have reagent burgling, which is epidemic at all levels of bench chemistry. No one has everything to hand, and you always run out of things. The stockroom may be some distance away, or take too much time, or there may be only one bottle of 2-methyl bromowhatsicene in the lab (and you don't have it). This can be innocent, as in taking 500mg of some common reagent out of a large bottle that someone has handy. Or it can be more serious (but still well-intentioned), in the "I'm going to bring it right back" way. Further down the scale, you have plain nastiness, of the "I need this and screw the rest of you" kind. I told the story here of having had most of a fresh bottle of borane/THF jacked from me, and you know, that happened in 1986 and I'm still a little cheesed off about it. Many readers will have experienced similar sensations.
Once, during my grad school days, I went off on a rare vacation and left notes in the various drawers of my bench. "It's not here!" read one of them, and another advised people "Take this from (fellow student X). He has a lot more of them than I do". When I came back, people told me that they enjoyed my notes. There you have it.
For Friday afternoon, I thought I'd put up another color post. That's nickel (II) chloride hydrate, and the only time I've used it was in a modified borohydride reduction. But that was a glorious prep, at least until the borohydride went in and everything turned black. Nickel chloride in methanol is as green as it gets - that's another one that I'm going to have just take a photo of sometime.
It's fake-looking, like some sort of dye, especially when you see it in an organic chemistry lab. Green is one of the harder colors for "normal" organic compounds to take on, so a vivid lime-gelatin-mix reaction really stands out. Does anyone have any other candidates?
For Friday afternoon, a bit of chem-geekery. I recently had occasion to use some copper sulfate, and the bottle I had was marked "large crystals" of the pentahydrate. I have loved the color of that stuff since I was a kid, and still do. Powdered, you lose a lot of the effect, but the chunks of crystalline stuff are the very definition of blue. (Photo from egeorge96 on Flickr).
Does anyone know a better one? That's my candidate for the solid phase. In solution, the complex of copper II and pyridine is a good one, a bit more towards royal blue/purple. You can definitely see the change when the pyridine hits it. I can't find a photo of that one on the web; if anyone has one, I'll be glad to post it. More colors to come on other slow Friday afternoons.
Update: a rare gas-phase blue (!) from the comments. Never seen that before!
And another one from the comments: here's someone who really, really, really likes copper sulfate. Here's how it was done.
Well, it is a hard question, and I don't know the answer, either. On Twitter, See Arr Oh wonders:
Know that tangy smell that LAH / NaH give off? Is that oil volatiles, or trace H2 being formed from room moisture?
I'm not sure, but I'd be willing to bet that hydrogen has no smell at all - it would seem too small and too bereft of interactions to see off the nasal receptors. So my guess is mineral oil constituents in the case of sodium hydride, which I usually handle as the dispersion. Now, the lithium aluminum hydride is a dry powder, so in that case, I'd say that I'm smelling the real stuff, which can't be improving my nose very much. That lines up with Chemjobber's explanation: "It's the smell of your nose hairs being deprotonated." Any other guesses?
Have I mentioned recently what a pain the rear the Ullmann reaction is? Copper, in general? Consider it done, then. I'm trying to make biaryl ethers, not something I'd usually do, and these reactions are the traditional answer. One of my laws of the lab, though, is that when there are fifty ways of doing some reaction in the literature, it means that there's no good way to do it, and the Ullmann is the big, hairy, sweaty example of just that phenomenon. Even when it works, there are worries. But you have to get it to work first. . .
Here's a query that I received the other day that I thought I'd pass on to the readership: "What's the one journal article or book chapter that you'd assign to a class to show them what medicinal chemistry and drug discovery are really like?"
That's a tricky one, because (as in many fields) the "what it's really like" aspect doesn't always translate to the printed page. But I'd be interested in seeing some suggestions.
There's an interesting paper out in PLoS One, called "Inside the Mind of a Medicinal Chemist". Now, that's not necessarily a place that everyone wants to go - mine is not exactly a tourist trap, I can tell you - but the authors are a group from Novartis, so they knew what they were getting into. The questions they were trying to answer on this spelunking expedition were:
1) How and to what extent do chemists simplify the problem of identifying promising chemical fragments to move forward in the discovery process? 2) Do different chemists use the same criteria for such decisions? 3) Can chemists accurately report the criteria they use for such decisions?
They took 19 lucky chemists from the Novartis labs and asked them to go through 8 batches of 500 fragments each and select the desirable compounds. For those of you outside the field, that is, unfortunately, a realistic test. We often have to work through lists of this type, for several reasons: "We have X dollars to spend on the screening collection - which compounds should we buy?" "Which of these compounds we already own should still be in the collection, and which should we get rid of?" "Here's the list of screening hits for Enzyme Y: which of these look like useful starting points?" I found myself just yesterday going through about 350 compounds for just this sort of purpose.
They also asked the chemists which of a set of factors they used to make their decisions. These included polarity, size, lipophilicity, rings versus chains, charge, particular functional groups, and so on. Interestingly, once the 19 chemists had made their choices (and reported the criteria they used in doing so), the authors went through the selections using two computational classification algorithms, semi-naïve Bayesian (SNB) and Random Forest (RF). This showed that most of the chemists actually used only one or two categories as important filters, a result that ties in with studies in other fields on how experts in a given subject make decisions. Reducing the complexity of a multifactorial problem is a key step for the human brain to deal with it; how well this reduction is done (trading accuracy for speed) is what can distinguish an expert from someone who's never faced a particular problem before.
But the chemists in this sample didn't all zoom in on the same factors. One chemist showed a strong preference away from the compounds with a higher polar surface area, for example, while another seemed to make size the most important descriptor. The ones using functional groups to pick compounds also showed some individual preferences - one chemist, for example, seemed to downgrade heteroaromatic compounds, unless they also had a carboxylic acid, in which case they moved back up the list. Overall, the most common one-factor preference was ring topology, followed by functional groups and hydrogen bond donors/acceptors.
Comparing structural preferences across the chemists revealed many differences of opinion as well. One of them seemed to like fused six-membered aromatic rings (that would not have been me, had I been in the data set!), while others marked those down. Some tricyclic structures were strongly favored by one chemist, and strongly disfavored by another, which makes me wonder if the authors were tempted to get the two of them together and let them fight it out.
How about the number of compounds passed? Here's the breakdown:
One simple metric of agreement is the fraction of compounds selected by each chemist per batch. The fraction of compounds deemed suitable to carry forward varied widely between chemists, ranging from 7% to 97% (average = 45%), though each chemist was relatively consistent from batch to batch. . .This variance between chemists was not related to their ideal library size (Fig. S7A) nor linearly related to the number of targets a chemist had previously worked on (R2 = 0.05, Fig. S7B). The fraction passed could, however, be explained by each chemist’s reported selection strategy (Fig. S7C). Chemists who reported selecting only the “best” fragments passed a lower fraction of compounds (0.13±0.07) than chemists that reported excluding only the “worst” fragments (0.61±0.34); those who reported intermediate strategies passed an intermediate fraction of compounds (0.39±0.25).
Then comes a key question: how similar were the chemists' picks to each other, or to their own previous selections? A well-known paper from a few years ago suggested that the same chemists, looking at the same list after the passage of time (and more lists!) would pick rather different sets of compounds. Update: see the comments for some interesting inside information on this work.)Here, the authors sprinkled in a couple of hundred compounds that were present in more than one list to test this out. And I'd say that the earlier results were replicated fairly well. Comparing chemists' picks to themselves, the average similarity was only 0.52, which the authors describe, perhaps charitably, as "moderately internally consistent".
But that's a unanimous chorus compared to the consensus between chemists. These had similarities ranging from 0.05 (!) to 0.52, with an average of 0.28. Overall, only 8% of the compounds had the same judgement passed on them by at least 75% of the chemists. And the great majority of those agreements were on bad compounds, as opposed to good ones: only 1% of the compounds were deemed good by at least 75% of the group!
There's one other interesting result to consider: recall that the chemists were asked to state what factors they used in making their decisions. How did those compare to what they actually seemed to find important? (An economist would call this a case of stated preference versus revealed preference). The authors call this an assessment of the chemists' self-awareness, which in my experience, is often a swampy area indeed. And that's what it turned out to be here as well: ". . .every single chemist reported properties that were never identified as important by our SNG or RF classifiers. . .chemist 3 reported that several properties were important, for failed to report that size played any role during selections. Our SNG and RF classifiers both revealed that size, an especially straightforward parameter to assess, was the most important ."
So, what to make of all this? I'd say that it's more proof that we medicinal chemists all come to the lab bench with our own sets of prejudices, based on our own experiences. We're not always aware of them, but they're certainly with us, "sewn into the lining of our lab coats", as Tom Wolfe might have put it. The tricky part is figuring out which of these quirks are actually useful, and how often. . .
Here's a paper that I missed in Organic Process Research and Development earlier this year, extolling the virtues of sulfolane as a high-temperature polar solvent. I have to say, I've never used it, although I hear of it being used once in a while, mainly by people who are really having to crank the temperature on some poor reaction.
The only bad thing I've heard about it is its difficulty of removal. That high-boiling polar aprotic group all has this problem, of course (DMSO is no treat to get out of your sample sometimes, either, although it's so water-soluble that you always have sheer extraction on your side). But sulfolane is higher-boiling than all the rest (287C!), and it also freezes at about 28C, which could be a problem, too. (The paper notes that small amounts of water lower the freezing temperature substantially, and that 97/3 sulfolane/water is an article of commerce itself, probably for that reason). It has an unusual advantage, though, from a safety standpoint: it stands out from all the other polar aprotics as having remarkably poor skin penetration (as contrasted very much with DMSO, for example). It's more toxic than the others, but the skin penetration makes up for that, as long as you're not ingesting it some other way, which is Not Advised.
The paper gives a number of examples where this solvent proved to be just the thing, so I'll have to keep it in mind. Anyone out there care to share any hands-on experiences?
The discussion here last week about exaggerated reaction yields has gotten me thinking. I actually seem to go for long periods without ever calculating (or caring much) about the yields of my reactions.
That's largely because of the sort of medicinal chemistry work that I do - very early stage stuff, about as far back as you can get. For that work, I like to say that there are really only two yields: enough, and not enough. And if you can get product into a vial, or intermediate sufficient to make more needed analogs, then you have enough. I'd prefer that reactions work well, of course, but "well" is defined in my mind as much (or more) by how clean the product is than how much of it gets produced. A lower-yielding reaction whose product falls out ready to use seems nicer than a higher-yielding one that needs careful chromatography to get the red stuff out of it.
That's the opposite of the way I used to think when I was doing my grad school work, of course. Twenty-seven steps in a row will get you thinking very hard indeed about yields, especially later on in the synthesis. It occurs to you pretty quickly that if you take a 50% yield on something that took you two months to make, that you're pouring a month's effort into the red waste can. If you're going to take a nasty yield in a long sequence, it's much better to get it over with in step one. You'll see this effect at work in papers that just start off from a literature reference intermediate (the "readily available compound 3" syndrome), which can mean that compound 3 is a nasty prep which would besmirch the rest of the sequence were it included.
I'd certainly think differently were I in process chemistry, too, of course. And when I have to work downstream on a project, I do spare a thought for the ease of the chemistry, because that's closer to the point where my optimization colleagues will have to deal with what we produce. But back at the early stage, I have to admit, I really don't care all that much. The vast majority of the compounds that get made back there are not going to go anywhere, so whatever gets them made and tested quickly is a good thing. The elegant synthesis is the one that gets it out of the lab and down the hall, whatever the yield might be.
Over at Just Like Cooking, See Arr Oh has been organizing a "Chem Coach Carnival". He's asking chemists (blogging and otherwise) some questions about their work, especially for the benefit of people who don't do it (or not yet), and I'm glad to throw an entry into the pile:
Describe your current job
My current job is titled "Research Fellow", but titles like this are notoriously slippery in biotech/pharma. What I really do is work in very early-stage research, pretty much the earliest that a medicinal chemist can get involved in. I help to think up new targets and work with the biologists to get them screened, then work to evaluate what comes out of the screening. Is it real? Is it useful? Can it be advanced? If not, what other options do we have to find chemical matter for the target?
What do you do in a standard "work day?"
My work day divides between my office and my lab. In the office, I'm digging around in the new literature for interesting things that my company might be able to use (new targets, new chemistry, new technologies). And I'm also searching for more information on the early projects that we're prosecuting now: has anyone else reported work on these, or something like them? And there are the actual compound series that we're working on - what's known about things of those types (if anything?) Have they ever been reported as hits for other targets? Any interesting reactions known for them that we could tap into? There are broad project-specific issues to research as well - let's say that we're hoping to pick up some activity or selectivity in a current series by targeting a particular region of our target protein. So, how well has that worked out for other proteins with similar binding pockets? What sorts of structures have tended to hit?
In the lab, I actually make some of the new compounds for testing on these ongoing projects. At this stage in my career (I've been in the industry since 1989), my main purpose is not cranking out compounds at the bench. But I can certainly contribute, and I've always enjoyed the physical experience of making new compounds and trying new reactions. It's a good break from the office, and the office is a good break from the lab when I have a run of discovering new ways to produce sticky maroon gunk. (Happens to everyone).
This being industry, there are also meetings. But I try to keep those down to a minimum - when my calendar shows a day full of them, I despair a bit. Most of the time, my feelings when leaving a meeting are those of Samuel Johnson on Paradise Lost: "None ever wished it longer".
Note: I've already described what happens downstream of me - here's one overview.
What kind of schooling / training / experience helped you get there?
I have a B.A. and a Ph.D., along with a post-doc. But by now, those are getting alarmingly far back in the past. What really counts these days is my industrial experience, which is now up to 23 years, at several different companies. Over that time, I don't think I've missed out on a single large therapeutic area or class of targets. And I've seen projects fail in all sorts of ways (and succeed in a few as well) - my worth largely depends on what I've learned from all of them, and applying it to the new stuff that's coming down the chute.
That can be tricky. The failings of inexperience are well known, but experience has its problems, too. There can be a tendency to assume that you really have seen everything before, and that you know how things are going to turn out. This isn't true. You can help to avoid some of the pitfalls you've tumbled into in the past, but drug research is big enough and varied enough that new ones are always out there. And things can work out, too, for reasons that are not clear and not predictable. My experience is worth a lot - it had better be - but that value has limits, and I need to be the first person to keep that in mind.
How does chemistry inform your work?
It's the absolute foundation of it. I approach biology thinking like a chemist; I approach physics thinking like a chemist. One trait that's very strong in my research personality is empiricism: I am congenitally suspicious of model systems, and I'd far rather have the data from the real experiment. And those real experiments need to be as real as possible, too. If you say enzyme assay, I'll ask for cells. If you have cell data, I'll ask about mice. Mice lead to dogs, and dogs lead to humans, and there's where we really find out if we have a drug, and not one minute before.
In general, if you say that something's not going to work, I'll ask if you've tried it. Not every experiment is feasible, or even wise, but a surprising amount of data gets left, ungathered, because someone didn't bother to check. Never talk yourself out of an easy experiment.
Finally, a unique, interesting, or funny anecdote about your career
People who know me, from my wife and kids to my labmates, will now groan and roll their eyes, because I am a walking collection of such things. Part of it's my Southern heritage; we love a good story well told. I think I'll go back to grad school for this one; I'm not sure if I've ever told it here on the blog:
When I first got to Duke, I was planning on working for Prof. Bert Fraser-Reid, who was doing chiral synthesis of natural products using carbohydrate starting materials. In most graduate departments, there's a period where the new students attend presentations by faculty members and then associate themselves with someone that they'd like to work for. During this process, I wanted to set up an interview with Fraser-Reid, so I left a note for him to that effect, with my phone number. His grad students told me, though, that he was out of town (which was not hard to believe; he traveled a great deal).
That night I was back in my ratty shared house off of Duke's East Campus, which my housemates and I were soon to find out we could not afford to actually heat for the winter (save for a coal stove in the front room). And at 9 PM, I was expecting a call from a friend of mine at Vanderbilt, a chemistry=major classmate of mine from my undergraduate school (Hendrix) who knew that I was trying to sign up with Fraser-Reid's group. So at 9 PM sharp, the phone rings, and I pick it up to hear my friend's voice, as if through a towel held over the phone, saying that he was Dr. Fraser-Reid, at Duke.
Hah! Nice try. "You fool, he's out of town!" I said gleefully. There was a pause at the other end of the line. "Ah, is this Derek Lowe? This is Dr. Fraser-Reid, at Duke." And that's when it dawned on me: this was Dr. Fraser-Reid. At Duke. One of my housemates was in the room while this was going on, and he told me that he'd thought until then that watching someone go suddenly pale was just a figure of speech. The blood drained from my brain as I stammered out something to the effect that, whoops, uh, sorry, I thought that he was someone else, arrgh, expecting another call, ho-ho, and so on. We did set up an appointment, and I actually ended up in his group, although he should have known better after that auspicious start. This particular mistake I have not repeated, I should add. Ever restless and exploring, I have moved on to other mistakes since then.
. . .However, transitioning into corporate pharma was a big if not bigger challenge in some ways. It took a while to figure out how the system works and how to advance one's career and not get stuck in the lab.
Now this is a touchy subject, and it's two words in it that make it so: "advance" and "stuck". Pick one hundred chemists who start out in, say, industrial drug research at any given time (I know, bear with me - it's a thought experiment). Now observe them at the five year mark, the ten, and the twenty. What will you find? Some of them will no longer be employed, for sure - recent years make that certain, but honestly, it's always been certain. Some of that, remember, is voluntary. Some people find out, in any profession (once they start practicing it) that it's not actually what they want to do with their lives. It's better to find that out earlier than later. Or something that's clearly better might come along; there are any number of reasons for people to exit a field on their own power. But others true will have been acted on by an outside force, whether that force is their own difficulty in holding on to their position, or the industry's difficulty in holding on to as many people as it used to.
So among those still employed, what will you have? Some of them will have more direct reports than others, or more responsibility in other ways. People's abilities, opportunities, and motivations vary. As time goes on, some of the initial cohort will have definitely moved "out of the lab". But there are different reasons for this. The most common is what's usually called something like "the managerial track". Depending on the company, it's often the case that as people move to higher positions on the org chart, that they'll spend less time actually in the lab as opposed to their offices. In the traditional European drug research labs (especially the German and Swiss ones), this process started very quickly, sometimes on day one. And in general, the larger the company, the more likely it is that people have desk-only jobs as they move along.
But most companies like this also have a "scientific track", although it's sometimes used as a bit of dumping ground for people who (for whatever reason) are definitely not on the managerial track. That does tend to cut into the definition between the two, but the idea is to have somewhere to advance/promote people who don't want to head in the desk/management direction. It's here, I think, that the hard feelings start, because of this blurred boundary.
It's safe to say that some people who move into the managing-the-organization side of the business don't miss the lab work all that much, although some of them certainly do. And it's also safe to say that some of the people who stay on the scientific side would very much rather not have to deal with a stack of performance reviews, budget spreadsheets, making sure that everyone's up to date in the internal training database, and the like - but then again, some of them wouldn't mind that stuff at all, if anyone would give them a chance to mind it. To further complicate things, not everyone on the managerial side of the business is necessarily a good manager, just as not everyone on the lab side of it is a wonderful scientist. And people with longtime desk/office jobs are sometimes heard to say that they miss lab work, in a sort of "good old days" tone.
So you can get some pretty dismissive stuff, from both sides. These would include (but are not limited to) statements about being someone being "stuck in the lab" (as opposed to doing the really important work), or someone else being nothing but a paper pusher who's forgotten how research works (or perhaps never really knew to start with). I try to stay away from those sorts of statements, myself, but everyone in industry will know the sort of thing I'm talking about.
My own preferences? I have a hood, and I work in it. I'm not there all the time, but I'm expected (as are others like me) to produce in the lab as well as at my desk. And I do spend time at the desk, too, although I try to spend it on scientific issues - how do we prosecute the project for Target X? What are the chances for Project Y, and what do we do if it doesn't work out? What technology do we have (or does anyone have) to go after Target Z? Managerially, I've never had a long list of direct reports, nor a list of people reporting to me who also have people reporting to them, etc. I've been, it's fair to say, on the scientific ladder. But "stuck in the lab" is not a phrase I've ever applied to myself.
The key, I think, is to continue to learn and to keep up, no matter which side of the divide you might be. You should be performing at a level that you couldn't have earlier in your career, either way - dealing with issues that you wouldn't have been able to handle, bringing your experience to bear on new situations. The danger in having been around the block a number of times is that you can start to feel as if you know more than you do, or that you've seen pretty much everything before (neither of those is true). But you should definitely know more than you used to!
Over at Chemistry Blog, there's a post by Quintus on the synthesis of a complex natural product, FR-182877. The route is interesting in that it features a key Diels-Alder reaction, and the post mentions that this isn't a reaction that gets used much in industry.
True enough - that one and the Claisen rearrangement are the first reactions I think of in the category of "taught in every organic chemistry course, haven't run one in years". In the case of the Claisen, the number of years is now getting up to. . .hmm, about 26, I think. The Diels-Alder has shown up a bit more often for me, and someone in my lab was running one last year, but it was the first time she'd ever done it (after many years of drug discovery experience).
Why is that? The post I linked to suggested a good reason that one isn't done too often on scale: it can be unpredictably exothermic, and some of the reactants can decide to polymerize instead, which you don't want, either. That can be very exothermic, too, and leaves you with a reactor full of useless plastic gunk which will have to be removed with tools ranging from a scoop to a saw. This is a good time to adduce the benefits of flow chemistry, which has been successfully applied in such cases, and is worth thinking about any time you have a batch reaction that might take off on you.
But to scale something up, you need to have an interest in that structure to start with. There's another reason that you don't see so many Diels-Alders in drug synthesis, and it has to do with the sorts of molecules we tend to make. The cycloaddition gives you a three-dimensional structure with stereocenters, and medicinal chemistry, notoriously, tends to favor flat aromatic rings, sometimes very much to its detriment. Many drug discovery departments have taken the pledge over the years to try to cut back on the flatness and introduce more sp3 carbons, but it doesn't always take. (For one thing, if your leads are coming out of your screening collection, odds are you'll be starting with something on the flat end of the scale, because that's what your past projects filled the files with).
I think that fragment-based drug discovery has a better chance of giving you 3-D leads, but only if you pay attention while you're working on it. Those hits can sometimes be prosecuted in the flat-and-aryl style, too, if you insist. And I think it's fair to say that a lot of fragment hits have an aryl (especially a heteroaryl) ring in them, which might reflect the ease of assembling a fragment-sized library of compounds full of such. Even the fragment folks have been talking over the years about the need to get more three-dimensionality into the collections, and vendors have been pitching this as a feature of their offerings.
The other rap on the classic Diels-Alder reaction is that it gives you substituted cyclohexanes, which aren't always the first place you look for drug leads. But the hetero-Diels-Alder reactions can give you a lot of interesting compounds that look more drug-like, and I think that they deserve more play than they get in this business. I'll go ahead and take a public pledge to run a series of them before the year is out!
Hang around a bunch of medicinal chemists (no, really, it's more fun than you'd think) and you're bound to hear discussion of cLogP. For the chemists in the crowd, I should warn you that I'm about to say nasty things about it.
For the nonchemists in the crowd, logP is a measure of how greasy (or how polar) a compound is. It's based on a partition experiment: shake up a measured amount of a compound with defined volumes of water and n-octanol, a rather greasy solvent which I've never seen referred to in any other experimental technique. Then measure how much of the compound ends up in each layer, and take the log of the octanol/water ratio. So if a thousand times as much compound goes into the octanol as goes into the water (which for drug substances is quite common, in fact, pretty good), then the logP is 3. The reason we care about this is that really greasy compounds (and one can go up to 4, 5, 6, and possibly beyond), have problems. They tend to dissolve poorly in the gut, have problems crossing membranes in living systems, get metabolized extensively in the liver, and stick to a lot of proteins that you'd rather they didn't stick to. Fewer high-logP compounds are capable of making it as drugs.
So far, so good. But there are complications. For one thing, that description above ignores the pH of the water solution, and for charged compounds that's a big factor. logD is the term for the distribution of all species (ionized or not), and logD at pH 7.4 (physiological) is a valuable measurement if you've got the possibility of a charged species (and plenty of drug molecules do, thanks to basic amines, carboxylic acids, etc.) But there are bigger problems.
You'll notice that the experiment outlined in the second paragraph could fairly be described as tedious. In fact, I have never seen it performed. Not once, and I'll bet that the majority of medicinal chemists never have, either. And it's not like it's just being done out of my sight; there's no roomful of automated octanol/water extraction machines clanking away in the basement. I should note that there are other higher-throughput experimental techniques (such as HPLC retention times) that also correlate with logP and have been used to generate real numbers, but even those don't account for the great majority of the numbers that we talk about all the time. So how do we manage to do that?
It has to do with a sleight of hand I've performed while writing the above sections, which some of you have probably already noticed. Most of the time, when we talk about logP values in early drug discovery, we're talking about cLogp. That "c" stands for calculated. There are several programs that estimate logP based on known values for different rings and functional groups, and with different algorithms for combining and interpolating them. In my experience, almost all logP numbers that get thrown around are from these tools; no octanol is involved.
And sometimes that worries me a bit. Not all of these programs will tell you how solid those estimates are. And even if they will, not all chemists will bother to check. If your structure is quite close to something that's been measured, then fine, the estimate is bound to be pretty good. But what if you feed in a heterocycle that's not in the lookup table? The program will spit out a number, that's what. But it may not be a very good number, even if it goes out to two decimal places. I can't even remember when I might have last seen a cLogP value with a range on it, or any other suggestion that it might be a bit fuzzy.
There are more subtle problems, too - I've seen some oddities with substitutions on saturated heterocyclic rings (morpholine, etc.) that didn't quite seem to make sense. Many chemists get these numbers, look at them quizzically, and say "Hmm, I didn't know that those things sorted out like that. Live and learn!" In other words, they take the calculated values as reality. I've even had people defend these numbers by explaining to me patiently that these are, after all, calculated logP values, and the calculated log P values rank-order like so, and what exactly is my problem? And while it's hard to argue with that, we are not putting our compounds into the simulated stomachs of rationalized rodents. Real-world decisions can be made based on numbers that do not come from the real world.
I was using a tertiary amine the other day when the thought occurred to me: these things all smell the same. The amine smell is instantly recognizable, fishy and penetrating, in the same way that sulfur smells are also easy to pick out (rotten egg/skunk/burning rubber and worse). But as the triethylamine smell wafted along, I began to think that the sulfur stenches cover a wider range than the amine ones.
Is that so? Sulfur compounds certainly have the bigger reputation for strong smells, and it's well earned. But I still have the impression that various thiols or low-molecular sulfides are easier to distinguish from each other. They all have that sulfur reek to them, but in subtle and ever-varying ways. I sound like a wine critic. Amines, though, tend to be a big more one-note. Fish market, they say. Low tide. I'm not sure I could tell triethylamine from Hünig's base from piperidine in a blind snort test, not that I'm totally motivated to try.
There are exceptions. The piperazines often take on a musty, dirt-like smell that overrides the fishy one. (Note, however, that the classic "dirt" smell is largely produced by a compound that has no nitrogen atoms in it at all). And when they first encounter pyrrolidine, chemists (especially male ones) are generally taken aback. (Now that I think about it, does piperdine smell more like pyrrolidine or like the generic tertiary amines?) The straight-chain diamines should be singled out, too, for their famously stinky qualities. If you've never encountered them, the mere existence of compounds with names like putrescine and cadaverine should be warning enough.
We should probably leave pyridine out of the discussion, since as an aromatic ring it's in a different class. But it has to be noted that its odor is truly vile and alien, smelling (fortunately) like nothing on earth except pyridine. These examples are enough, though, to make me wonder if I'm short-changing the amines when I don't rate them as highly for range and versatility in the chemical odor department. Examples are welcome in the comments of amines that go beyond the Standard Mackeral. . .
A couple of commenters took exception to my words yesterday about thiophene not being a "real" heterocycle. And I have to say, on reflection, that they're right. When I think about it, I have seen an example myself, in a project some years ago, where thiophene-for-phenyl was not a silent switch. If I recall correctly, the thiophene was surprisingly more potent, and that seems to be the direction that other people have seen as well. Anyone know of an example where a thiophene kills the activity compared to a phenyl?
That said, the great majority of the times I've seen matched pairs of compounds with this change, there's been no real difference in activity. I haven't seen as many PK comparisons, but the ones I can think of have been pretty close. That's not always the case, though: Plavix (clopidogrel) is the canonical example of a thiophene that gets metabolically unzipped (scroll down on that page to "Pharmacokinetics and metabolism" to see the scheme). You're not going to see a phenyl ring do that, of course - it'll get oxidized to the phenol, likely as not, but that'll get glucuronidated or something and sluiced out the kidneys, taking everything else with it. But note also that depending on things like CYP2C19 to produce your active drug for you is not without risks: people vary in their enzyme profiles, and you might find that your blood levels in a real patient population are rather jumpier than you'd hoped for.
So I'll take back my comments: thiophene really is (or at least can be) a heterocycle all its own, and not just a phenyl with eye makeup. But one of the conclusions of that GSK paper was that it's not such a great heterocycle for drug development, in the end.
Here's a paper from some folks at GlaxoSmithKline on what kinds of rings seem to have the best chances as parts of a drug structure. They're looking at replacements for plain old aryl rings, of which there are often too many. Pulling data out of the GSK corporate collection, they find that the most common heteroaromatic rings are pyridine, pyrazole, and pyrimidine - together, those are about half the data set. (The least common, in case you're wondering, are 1,3,5-triazine, 1,3,4-oxadiazole, and tetrazole). In marketed drugs, though, pyridine is more of a clear winner, and both pyrrole and imidazole make the top of the charts as well.
When they checked the aqueous solubility of all these compounds, the 1,2,4-triazoles came out on top, and the 1,3,5-triazines were at the bottom, which sounds about right. Other soluble heterocycles included 1,3,4-oxadizole and pyridazine, and other bricks were thiazole and thiophene (not that that last one really counts as a heterocycle in my book). Update: I've revised my thoughts on that! Now, you might look at these and say "Sure, and you could have saved yourself the trouble by just looking at the logD values - don't they line up?" They do, for the most part, but it turns out that the triazines are unusually bad for their logDs, while the five-membered rings with adjacent nitrogens (all of 'em) were unusually good.
The next thing the team looked at was binding to human serum albumin. The 1,3,4-thiadiazoles emerged as the losers here, with by far the most protein binding, followed by thiazoles and 1,2,4-oxadiazoles. Imidazoles had the least, by a good margin, followed by pyrazine and pyridazine. Those last two were better than expected compared to their logD values.
And the last big category was CYP450 inhibition. Here, thiophene, tetrazole, and 1,2,3-triazole were the bad guys, and pyridazine, 1,3,4-thiadizole, and pyrazine (and a few others) were relatively clean. The people at AstraZeneca have published a similar analysis, and the two data sets agree pretty well, with the exception of oxazole and tetrazole. The AZ oxazoles all had open positions next to the ring nitrogen, which seems to have opened them up to metabolism, but the difference in tetrazoles (AZ good, GSK bad) is harder to explain.
The take-home? Pyridazine, pyrazine, imidazole and pyrazole look like the winners from an overall "developability" score. Thiophene brings up the rear, but since I still think that one shouldn't count update (it's a benzene in disguise), the ones to worry about are then thiazole, 1,2,3-triazole, and tetrazole (that last one with an asterisk, due to the CYP data discrepancy).
The paper tries to do the same analysis with heteroaliphatic rings, but the authors admit that they had a much smaller data set to work with, so the conclusions aren't as strong. There was also a higher correlation with plain ol' logD values across all three categories (not as many surprises). The winners turned out to be piperidine NH and morpholine N-alkyl, with imidazoline and piperidine N-alkyl right behind. The losers? Piperidine N-sulfonamide, followed by pyrrolidine N-sulfonamide, and then 1,3-thiazolidine. (Sulfonamides continue to live up - or down - to their reputation as Bad News).
There are, naturally, limitations to this sort of thing. Ceteris paribus is a mighty difficult state of affairs to achieve in medicinal chemistry, and other factors can rearrange things quickly. But if you're just starting out in an SAR series, it sounds like you might wand to give the pyrazines and pyridazines a look.
With all the electronic notebooks around these days, and the ubiquity of computer hardware and keyboards around the HPLCs, LC/mass specs, and so on, I'm surprised that we don't see more of this. But that is the first keyboard I've seen melted in a lab setting - perhaps I'm just leading a sheltered life.
But ginger ale in an Apple wireless keyboard? I can get that at home, courtesy of my kids. (The hardware survived, although some of the keys were a bit crunchy for a while. . .)
There are a number of structures that I've never been quite able to make up my mind about in medicinal chemistry. One of those is the pyridine N-oxide. You really don't see those in drugs (at least, no examples come to mind), but you don't see many people trying to advance them as drugs, either. Note: the first comment points out the two key examples I'd forgotten: librium and minoxidil. Once in a while they turn up in the literature, often never to be seen again. I believe that one problem with them is that they present in a living system as mild oxidizing agents, which is the sort of thing that cells try to avoid, and I can't imagine that their pharmacokinetics are very appealing either. There are quite a few pyridine derivatives that are turned into their N-oxides on the way to being excreted, which makes you think that bringing one in from the the start is greasing the skids for fast clearance. But I've never seen one dosed, so how would I know for sure?
These thoughts are prompted by this paper from J. Med. Chem., which has an even stranger-looking benzotriazine bis-oxide. These compounds seem quite active against drug-resistant tuberculosis strains (and it's always good to see something that can kill those guys off), but I'll watch with interest to see if they can be developed into drugs. Anyone else out there ever had the nerve to push an N-oxide forward?
Chemistry moves on, and it doesn't always take everything with it. There are reagents and reactions that used to be all over the literature, but have fallen out of use, superseded by easier or more reliable alternatives. The first thing I think of in this category is pyridinium chlorochromate (PCC), which I wrote about here. That was all the rage in the late 1970s and into the 1980s, but I don't know when I've last seen a bottle of the stuff.
And since that post itself is seven years old now, I wanted to throw the floor open again for a discussion of dead reagents and dusty reactions. There are plenty of obscure ones, of course, and plenty that don't get much use but still have their place in special situations. But I'm wondering about the ones that used to be big and now are disappearing. What are some that you used to use, but never expect to again?
For my part, other than PCC, I don't ever see doing a vanadium-catalyzed epoxidation, even though I did a few in grad school. And I recall doing a Jones oxidation - does anyone use that one any more? Another reagent that had a vogue in the late 1980s and early 1990s, but I don't recall seeing any time recently, was tris(trimethylsilyl)silane (a replacement for tri-n-butyltin hydride). So those are my nominees - what else?
You chemists may have really stretched things to get a reaction to work, but here's a good set of "Conditions You'll Probably Never Be Desperate Enough to Try". Bone meal? Ground carrots? I think he has a point.
Let's file this one under "Cultural Differences Between Chemists and Biologists". Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?
It's struck me several times over the years. Biologists seem, on average, to go into much more granular detail about their experiments when presenting to a mixed audience than do most chemists. Buffers, buffers that worked a little better, buffers that worked a bit worse, the brand of the sizing column, western blot after western blot. The usual chemistry comment was always "Hey, I don't show pictures of my TLC plates", but eventually I suppose we'll need to come up with another line as LC/MS takes over the world.
Even presenting among their own tribe, most chemists don't (to me) seem to go to the level of detail that I often see from protein purification people or pharmacologists. My theory is that most forms of biology still have so many hidden variables in them (since it's an intrinsically more complex and less understood science) that all the details need to be specified. Organic chemistry, for all its troubles, still tends to be more reproducible, on average, than molecular biology, and at a less picky level of detail
That's why chemists don't often feel the need to go into details even in a room full of chemists: "We had the bromide, so we made these coupled products, and then we made these by reductive amination. . ." substitutes for "We had the aryl bromide, so we reacted it with a list of boronic acids under palladium-catalyzed coupling conditions to give these products, each of which still has the aldehyde in the 3-position, which we purified by chromatography in an ethyl acetate/hexane gradient over 8-gram ISCO silica gel cartridges. We then reacted them with a list of amines using sodium triacetoxyborohydride in dichloromethane at room temperature, followed by a chromatography in 1 to 5% methanol/dichloromethane. . . ". Each of those steps has plenty of other options - different reagent combinations, solvents, etc., and if some colleague needs to reproduce your work, they'll check your notebook or ask you "Hey, what did you guys use for those Suzukis? Dppf? Yuck."
We certainly won't go into that level of detail in a room half full of biologists - it's mostly "We made these, and these, and these", which spares everyone. No TLC plates, no LC/MS traces, no NMR spectra. But they're available if you want 'em.
I wanted to call attention to a piece by Bruce Booth over at Forbes. He starts off from the Scannell paper in Nature Reviews Drug Discovery that we were discussing here recently, but he goes on to another factor. And it's a big one: culture.
Fundamentally, I think the bulk of the last decade’s productivity decline is attributable to a culture problem. The Big Pharma culture has been homogenized, purified, sterilized, whipped, stirred, filtered, etc and lost its ability to ferment the good stuff required to innovate. This isn’t covered in most reviews of the productivity challenge facing our industry, because its nearly impossible to quantify, but it’s well known and a huge issue.
You really should read the whole thing, but I'll mention some of his main points. One of those is "The Tyranny of the Committee". You know, nothing good can ever be decided unless there are a lot of people in the room - right? And then that decision has to move to another room full of people who give it a different working-over, with lots more PowerPoint - right? And then that decision moves up to a group of higher-level people, who look at the slides again - or summaries of them - and make a collective decision. That's how it's supposed to work - uh, right?
Another is "Stagnation Through Risk Avoidance". Projects go on longer, and keep everyone busy, if the nasty issues aren't faced too quickly. And everyone has room to deflect blame when things go wrong, if plenty of work has been poured into the project, from several different areas, before the bad news hits. Most of the time, you know, some sort of bad news is waiting out there, so you want to have yourself (and your career) prepared beforehand - right? After all, several high-level committees signed off on this project. . .
And then there's "Organizational Entropy", which we've discussed around here, too. When the New, Latest, Really-Going-to-Work reorganization hits, as it does every three years or so, things slow down. They have to. And a nice big merger doesn't just slow things down, it brings everything to a juddering halt. The cumulative effect of these things can be deadly.
As Booth says, there are other factors as well. I'd add a couple to the list, myself: the tendency to think that If This Was Any Good, Someone Else Would Be Doing It (which is another way of being able to run for cover if things don't work out), and the general human sunk-cost fallacy of We've Come This Far; We Have to Get Something Out of This. But his main point stands, and has stood for many years. The research culture in many big drug companies stands in the way of getting things done. More posts on this to follow.
A reader sent along this question for the medicinal chemists in the crowd: we spend a lot of time thinking about what makes a molecule ugly (by our standards). But what about the flip side? What makes a molecule beautiful?
That's a hard one to answer, because, well, eye of the beholder and all that. One answer is that if it works well as a drug, how ugly can it be? (See the recent post here about the ugliest drugs in that light). Then there are all sorts of striking molecular structures that have nothing to do with medicinal chemistry, but for the purposes of today's discussion, I think we should rule those out. So, what makes a drug molecule (or candidate molecule) beautiful?
Size matters, for one thing. It may be my bias towards ligand efficiency, but I'm more impressed with potent, selective molecules that can get the job done with lower molecular weight. And you know that in a huge structure, a lot of the atoms are just scaffolding to get the business end(s) of the molecule in the right place, and I can't see giving points for that.
Points should also go for originality. I enjoy seeing a functional motif that hasn't turned up in a dozen other drugs. That may be because I can imagine that the team that developed the compound probably ran through the more usual stuff first and ended up having to go with the newer-looking group, in spite of their own reservations about what might happen. For similar reasons, I also have a bias towards three-dimensional character. Drug binding pockets are generally 3-D (and chiral), so a compound that takes advantage of those seems more elegant than a completely flat structure. (Although you can argue that a flat structure that works is easier to make, and that's definitely not a trivial consideration).
These tend to lead me, when I look though tables of drugs, to CNS ligands, and perhaps that reflects the influence of my first few years in the industry. But for whatever reason, something like escitalopram just looks like a drug molecule to me. As came up in the "ugly drug" post, though, it's instructive to look over a list of, say, the 200 biggest-selling compounds and realize how many structures a person can find aesthetic fault with. Which shows you how far you can get with aesthetics in this business. . .
Which reminds me: coming soon is a large post with graphics of many of the nominated compounds in the "ugliest drug" category. It'll be worth looking them over, and reflecting that they're out there treating patients and making money.
A recent discussion with colleagues turned around the question: "Would you rather succeed ugly or fail gracefully?" In drug discovery terms, that could be rephrased "Would you rather get a compound through the clinic after wrestling with a marginal structure, worrying about tox, having to fix the formulation three times, and so on, or would you rather work on something that everyone agrees is a solid target, with good chemical matter, SAR that makes sense, leading to a potent, selective, clean compound that dies anyway in Phase II?"
I vote for option number one, if those are my choices. But here's the question at the heart of a lot of the debates about preclinical criteria: do more programs like that die, or do more programs like option number two die? I tend to think that way back early in the process, when you're still picking leads, that you're better off with non-ugly chemical matter. We're only going to make it bigger and greasier, so start with as pretty a molecule as you can. But as things go on, and as you get closer to the clinic, you have to face up to the fact that no matter how you got there, no one really knows what's going to happen once you're in humans. You don't really know if your mechanism is correct (Phase II), and you sure don't know if you're going to see some sort of funny tox or long-term effect (Phase III). The chances of those are still higher if your compound is exceptionally greasy, so I think that everyone can agree that (other things being equal) you're better off with a lower logP. But what else can you trust? Not much.
The important thing is getting into the clinic, because that's where all the big questions are answered. And it's also where the big money is spent, so you have to be careful, on the other side of the equation, and not just shove all kinds of things into humans. You're going to run out of time and cash, most likely, before something works. But if you kill everything off before it gets that far, you're going to run out of both of those, too, for sure. You're going to have to take some shots at some point, and those will probably be with compounds that are less than ideal. A drug is a biologically active chemical compound that has things wrong with it.
There's another component to that "fail gracefully" idea, though, and it's a less honorable one. In a large organization, it can be to a person's advantage to make sure that everything's being done in the approved way, even if that leads off the cliff eventually. At least that way you can't be blamed, right? So you might not think that an inhibitor of Target X is such a great idea, but the committee that proposes new targets does, so you keep your head down. And you may wonder about the way the SAR is being prosecuted, but the official criteria say that you have to have at least so much potency and at least so much selectivity, so you do what you have to to make the cutoffs. And on it goes. In the end, you deliver a putative clinical candidate that may not have much of a chance at all, but that's not your department, because all the boxes got checked. More to the point, all the boxes were widely seen to be checked. So if it fails, well, it's just one of those things. Everyone did everything right, everyone met the departmental goals: what else can you do?
This gets back to the post the other day on unlikely-looking drug structures. There are a lot of them; I'll put together a gallery soon. But I think it's important to look these things over, and to realize that every one of them is out there on the market. They're on the pharmacy shelves because someone had the nerve to take them into the clinic, because someone was willing to win with an ugly compound. Looking at them, I realize that I would have crossed off billions of dollars just because I didn't feel comfortable with these structures, which makes me wonder if I haven't been overvaluing my opinion in these matters. You can't get a drug on the market without offending someone, and it may be you.
So how do we deal with the piles of data? A reader sent along this question, and it's worth thinking about. Drug research - even the preclinical kind - generates an awful lot of information. The other day, it was pointed out that one of our projects, if you expanded everything out, would be displayed on a spreadsheet with compounds running down the left, and over two hundred columns stretching across the page. Not all of those are populated for every compound, by any means, especially the newer ones. But compounds that stay in the screening collection tend to accumulate a lot of data with time, and there are hundreds of thousands (or millions) of compounds in a good-sized screening collection. How do we keep track of it all?
Most larger companies have some sort of proprietary software for the job (or jobs). The idea is that you can enter a structure (or substructure) of a compound and find out the project it was made for, every assay that's been run on it, all its spectral data and physical properties (experimental and calculated), every batch that's been made or bought (and from whom and from where, with notebook and catalog references), and the bar code of every vial or bottle of it that's running around the labs. You obviously don't want all of those every time, so you need to be able to define your queries over a wide range, setting a few common ones as defaults and customizing them for individual projects while they're running.
Displaying all this data isn't trivial, either. The good old fashioned spreadsheet is perfectly useful, but you're going to need the ability to plot and chart in all sorts of ways to actually see what's going on in a big project. How does human microsomal stability relate to the logP of the right-hand side chain in the pyrimidinyl-series compounds with molecular weight under 425? And how do those numbers compare to the dog microsomes? And how do either of those compare to the blood levels in the whole animal, keeping in mind that you've been using two different dosing vehicles along the way? To visualize these kinds of questions - perfectly reasonable ones, let me tell you - you'll need all the help you can get.
You run into the problem of any large, multifunctional program, though: if it can do everything, it may not do any one thing very well. Or there may be a way to do whatever you want, if only you can memorize the magic spell that will make it happen. If it's one of those programs that you have to use constantly or run the risk of totally forgetting how it goes, there will be trouble.
So what's been the experience out there? In-house home-built software? Adaptations of commercial packages? How does a smaller company afford to do what it needs to do? Comments welcome. . .
The carbonyl group is one of the most fundamental structure in organic chemistry: C-double-bond-O. But you can substitute that oxygen with a sulfur and get to a whole new series of compounds - so how come we don't see so many of those in drugs?
Well, not all of them are stable. Plain old thioketones are pretty reactive, not to mention their appalling stink. And even though they're not as bad as thioketones, the corresponding thioamides and thioureas are known to be more lively than their oxygen counterparts. Many medicinal chemists avoid them because of a reputation for trouble, which I think is probably earned and not just an irrational prejudice. But there are drugs and pharmacological tools with these structures, still.
The thiocarbonyl shows up in a number of heterocycles, too, and there the situation gets a bit murkier. The highest-profile member of this group, unfortunately, may well be the rhodanines, which have come up several times on this blog, most recently here. I'm not a fan of those guys, but here's a question: are there thiocarbonyl structures that are better behaved? Do people like me look down on the whole functional group because of a few (well, more than a few) bad actors?
The large number of comments on yesterday's post on Sanofi CEO Chris Viehbacher's relentless candid interview included a response from someone at the company itself. At least, I have to assume that it is indeed Jack Cox, Senior Director of Public Affairs and Media Relations (as his LinkedIn profile has it), since the name and position match up, and the IP address of the comment resolves to Sanofi-US. I wanted to highlight his response - in the interest of fairness - and the responses to it, without having everything buried in the triple-digit comments thread to the previous post. Says Mr. Cox:
Anyone who has followed Chris in recent months will have heard some variation of these comments, but within the broader context that unfortunately didn't make it into the Q&A you reference.
Chris has consistently said that his vision for Sanofi's R&D organization is one of open collaboration, in which our own researchers increasingly partner with external teams. This is consistent with a comment you've included: "We're not going to get out of research. We believe we do things will in research but we want to work with more outside companies, startup biotechs, with universities."
In an interview with Luke Timmerman published by Xconomy in January Chris explained how this is working in practice:
"In Cambridge, you've got all those things. Being the No. 1 life sciences employer in Boston is great, but we didn't want to just do the same thing we did everywhere else, having everybody inside our walls. So we created this concept of a hub. There's a core, with a lot of competencies that a big organization can bring, but the idea of a hub is that we can manage the relationships we have with everybody from Dana-Farber Cancer Institute to Harvard to MIT to the Joslin Diabetes Center to some of the biotechs we work with. And we put our own oncology research team in Cambridge. There's a whole ecosystem in Boston, and we feel integrated and at the center of it."
Seeking external expertise, particularly when it concerns emerging technologies, contributes to the creativity and innovation we have within. The key to our approach, however, is that we don't want to simply be investors, but true partners. Again, consider the broader context as shared with Luke:
"The Warp Drive Bio project is interesting because it demonstrates where we want to go. It was very much on the basis of saying we want to work with (Harvard University chemical biologist) Greg Verdine. Someone like that isn't going to come work for Big Pharma, but we liked the science he was doing. We have a strong interest and expertise in natural products, and he had a genomics screening tool.
We will contribute expertise. I don't want to be a venture capitalist, or have a venture fund, like some other companies do. But I want to actually partner, where we bring some of what we know, and combine it with what Warp Drive has. The fact that we are trying to bring people from Sanofi into the collaboration, at such an early stage of research, is unusual. The single factor for success will be whether you can take a company like Warp Drive, with a handful of people, and make it work with an organization of 110,000 people without smothering it."
I believe your readers will agree that in this case the context really matters. Relying on one incomplete source doesn't do justice to the overall approach Chris has been describing.
If you want to truly understand the vision Chris has for Sanofi's research organization, I invite you to catch one of his public speaking engagements in the Boston area.
One has to wonder if the main difference between the two interviews was that Viehbacher spent more time considering his replies to Xconomy. I take it that since there's been no attempt to deny the earlier quotes in MedCityNews, that they're authentic. And the problem is, even some of his less popular statements in that interview are not false. It really is harder to innovate in a big company compared to a smaller one, for example. But while not false, they're also not the sort of thing one would expect the CEO of a major drug company to just blurt out, either, especially considering the likely effects of such statements on his own company's morale. I believe, in fact, that some current and (recently) ex-Sanofi employees have comments to make on that issue.
In case you're a scientist, and especially if you're a scientist at Sanofi, their CEO Chris Viehbacher would like you to know some things. What things are those, you ask? Well, how about your position in the world, and especially your position at Sanofi itself?
"What Sanofi is doing is reducing its own internal research capacity. The days when we locked all of our scientists up in a building and put them on a nice tree-lined campus are done. We will do less of our own research. We’re not going to get out of research. We believe we do certain things well in research but we want to work with more outside companies, startup biotechs, with universities."
You know, people with real ideas, innovative stuff, that kind of thing. When asked if this was cheaper, Viehbacher replied:
"It is cheaper. But research and development is either a huge waste of money or too, too valuable. It’s not really anything in between. You don’t really do things because it’s cheaper. The reality is the best people who have great ideas in science don’t want to work for a big company. They want to create their own company. So, in other words, if you want to work with the best people, you’re going to have go outside your own company and work with those people … And, you want to work with them, why do they want to work with you? The reality over the last 10 years is, (a small biotech) wouldn’t get caught dead working with one of these big cumbersome pharma companies. Once you have a funding gap, suddenly there’s a much greater willingness of earlier-stage companies to work with Big Pharma. We’re looking earlier and people who are early need help.
So, if you're one of Sanofi's dwindling number of internal scientists, at least now you know what you're being treated the way you are. It's because you're, well, you're not the sharpest tool in the shed. If your company really wants something to happen, they'll need to bypass you and find someone good. Sticking you in a nice building and telling you to discover stuff hasn't worked out, clearly, and blame must be attached somewhere. Right?
At least Viehbacher has enough self-knowledge to know what people outside his company thinks of it (and its ilk). But hey, now that the people who can actually discover things are desperate, opportunity knocks! This is a business plan known as "So, you need a deal real bad? Well, here's a really bad deal!" And it's the sort of arrangement that just makes everyone happy all around. When asked about working with venture capital firms (as Sanofi recently did with the unfortunately named Warp Drive Bio), the response was:
"There’s two reasons I like (working with venture capital firms). One is, they can sometimes bring competencies we don’t have, like for instance in how to help a startup company. The second thing is to give you a second opinion. Somebody in your company is going to love the science and be championing this internally. But you want to have a second opinion. If you have a venture capital company that’s willing to put money in, that kind of gives a little validation of that."
Those people in his own company again! Nothing but trouble. You wonder, though, what happens when someone inside Sanofi thinks that some hot startup deal might not be a good idea. I wonder if everyone was in love with Warp Drive Bio, for example? No matter - a VC firm was willing to put actual money into the thing, so that's pretty much all the validation anyone needs. Investors in the public markets, though, are apparently fools, because they think that because a big pharma company is interested, that means that a small company might have something going for it:
"The new model, where we’re trying to go, we believe that Big Pharma has competencies in validation. So, if a Big Pharma company does a deal with a smaller company, the smaller company’s share price goes up because people believe that Big Pharma has depth of competencies to judge whether this science is any good or not. Now big companies, and not just Big Pharma, big companies I believe, are not any good at doing innovation. There has to be some element of disruptive thinking to have innovation and I can tell you that big companies do everything to avoid any disruptive thinking in their companies."
Hah! The investors should read Viehbacher's interview, and realize that the sort of scientists who work inside a big company like his wouldn't know an innovation if it slithered up their leg.
Now, there are points to be made about large organizations, and about disruptive thinking, and about various models for drug discovery and for funding ideas. But you know, at the moment, I'm too disgusted to make them.
Update: comments have been disabled now, due to the large volume of them and the follow-up post. Any thoughts can be directed over there - thanks!
I wrote here about a very unusual dinitro compound that's in the clinic in oncology. Now there's a synthetic chemistry follow-up, in the form of a paper in Organic Process R&D.
It's safe to say that most process and scale-up chemists are never going to have to worry about making a gem-dinitroazetidine - or, for that matter, a gem-dinitroanything. But the issues involved are the same ones that come up over and over again. See if this rings any bells:
Gram quantities of (3) for initial anticancer screening were originally prepared by an unoptimized approach that was not suitable for scale-up and failed to address specific hazards of the reaction intermediates and coproducts. The success of (3) in preclinical studies prompted the need for a safe, reliable, and scalable synthesis to provide larger supplies of the active pharmaceutical ingredient (API) for further investigation and eventual clinical trials.
Yep, it's when you need large, reliable batches of something that the inadequacies of your chemistry really stand out. The kinds of chemistry that people like me do, back in the discovery labs, often has to be junked. It's fine for making 100mg of something to put in the archives - and tell me, when was the last time you put as much as 100 milligrams of a new compound into the archives? But there are usually plenty of weak points as you try to go to gram, then hundreds of grams, then kilos and up. Among them are:
(1) Exothermic chemistry. Excess heat is easy to shed from a 25-mL round-bottom flask. Heat is not so easily lost from larger vessels, though, and the number of chemists who have had to discover this the hard way is beyond counting. The world is very different when everything in the flask is no longer just 1 cm away from a cold glass wall.
(2) Stirring. This can be a pain even on the small scale, so imagine what a headache it is by the kilo. Gooey precipitates, thick milkshake-like reactions, lumps of crud - what's inconvenient when small can turn into a disaster later on, because poor stirring leads to localized heating (see above), incomplete reactions, side products, and more.
(3) Purification. Just run it down a column? Not so fast, chief. Where, exactly, do you find the columns to run kilos of material across? And the pumps to force the stuff through? And the wherewithal to dispose of all that solid-phase stuff once you've turned it all those colors and it can't be used again? And the time and money to evaporate all that solvent that you're using? No, the scale-up people will go a long way to avoid chromatography. Precipitations and crystallizations are the way to go, if at all possible.
Reproducibility. All of these factors influence this part. One of the most important things about a good chemical process is that it works the same flippin' way every single time. As has been said before around here, a route that generates 97% yield most of the time, but with an occasional mysterious 20% flop, is useless. Worse than useless. Squeezing the mystery out of the synthesis is the whole point of process chemistry: you want to know what the side products are, why they form, and how to control every variable.
Oh yeah. Cost.Cost-of-goods is rarely a deal-breaker in drug research, but that's partly because people are paying attention to it. In the med-chem labs, we think nothing of using exotic reagents that the single commercial supplier marks up to the sky. That will not fly on scale. Cutting out three steps with a reagent that isn't obtainable in quantity doesn't help the scale-up people one bit. (The good news is that some of these things turn out to be available when someone really wants them - the free market in action).
There are other factors, but those are some of the main ones. It's a different world, and it involves thinking about things that a discovery chemist just never thinks about. (Does your product tend to create a fine dust on handling? The sort that might fill a room and explode with static electricity sparks? Can your reaction mixture be pumped through a pipe as a slurry, or not? And so on.) It looks as if the dinitro compound has made it through this gauntlet successfully, but every day, there's someone at some drug company worrying about the next candidate.
Well, since I was just talking about a reagent that can potentially take off without warning, I wanted to solicit vivid experiences from the crowd. What's a compound that you've made that did something violently unexpected? I can recall making some para-methoxybenzyl chloride in grad school (for a protecting group; I was running out of orthogonal protecting groups by that time). It's not hard - take the benzyl alcohol and some conc. HCl and swoosh 'em around. But the product you get by that method isn't the cleanest thing in the world, and on storage, well. . .a vial of it blew out in my hood after the acid had had a chance to work on it.
My most vivid reagent-gone-bad story is probably this one; that's a time I literally came down counting fingers. What other things have you had turn on you?
Noted chem-blogger Milkshake seems to have had a close call with a fire started by a tiny potassium hydride residue. It looks like he made it through without serious injury, but that sort of thing will definitely shake a person up.
I hate potassium hydride. Its relative sodium hydride is a common reagent, but it's much tamer (and even so, can cause interesting fires - I knew someone who ignited a heap of it on the pan of a balance while he was weighing it out, which slowed things down a bit). Sodium hydride is usually sold as a 60% dispersion, a dark grey powder soaked with mineral oil to keep it from deteriorating too quickly (and to keep it from setting everything on fire). You can buy 95% sodium hydride, the dry stuff, and there are people who swear by it, but I tend to sweat at it. You never know if it's been stored properly; you may be adding a slug of sodium hydroxide to your reaction without knowing it. And there's the fire part. You'll want to move briskly if you're using the 95%, and I'd pick a day when the humidity is low.
But potassium hydride, that's another beast entirely. It makes the sodium compound look like corn meal, in terms of how forgiving it is. You can't get away with the clumpy oily powder form at all - traditionally, KH is sold as a gooey dispersion of grey powder sitting under a few inches of mineral oil. If it's well dispersed, it's supposed to be 35%. You shake the stuff up until you think it's even mixed, then pipet out the amount of gunk that corresponded to the KH contained therein. Sure you do. What actually happens is that you pipet out the stuff, noticing while you do that it's already settling out inside the pipet, thereby to clog it up when you try to transfer it. No fun.
It's becoming available now dispersed in a block of wax, which is not such a bad idea at all. Wax isn't any harder to get out of your reaction than oil is, and you can carve off chunks and weigh them without so many what-am-I-doing moments. But Milkshake worries that this ease of use will lead to more fires during workups (which is where his reaction ran into trouble), and he may well be right. If you're going to use KH, don't let your guard down.
Someone has been soaking up the atmosphere at a large pharma company, for sure. "Look, I'm a chemist. I thought you hired me to do chemistry. But so far, all I've heard is gibberish. . .don't you do chemistry here?".
Some of you may enjoy that, but for others, it might just be a bit too realistic to be amusing. . .
The same user has several other videos on YouTube, such as this one, which (in addition to a few four-letter words), features the phrase "Get off the Kool-Aid!" Clearly someone needs to go through some more training. (Thanks to Pharmalot for the original link).
There's a new paper out in Nature Chemistry called "Quantifying the Chemical Beauty of Drugs". The authors are proposing a new "desirability score" for chemical structures in drug discovery, one that's an amalgam of physical and structural scores. To their credit, they didn't decide up front which of these things should be the miost important. Rather, they took eight properties over 770 well-known oral drugs, and set about figuring how much to weight each of them. (This was done, for the info-geeks among the crowd, by calculating the Shannon entropy for each possibility to maximize the information contained in the final model). Interestingly, this approach tended to give zero weight to the number of hydrogen-bond acceptors and to the polar surface area, which suggests that those two measurements are already subsumed in the other factors.
And that's all fine, but what does the result give us? Or, more accurately, what does it give us that we haven't had before? After all, there have been a number of such compound-rating schemes proposed before (and the authors, again to their credit, compare their new proposal with the others head-to-head). But I don't see any great advantage. The Lipinski "Rule of 5" is a pretty simple metric - too simple for many tastes - and what this gives you is a Rule of 5 with both categories smeared out towards each other to give some continuous overlap. (See the figure below, which is taken from the paper). That's certainly more in line with the real world, but in that real world, will people be willing to make decisions based on this method, or not?
The authors go for a bigger splash with the title of the paper, which refers to an experiment they tried. They had chemists across AstraZeneca's organization assess some 17,000 compounds (200 or so for each) with a "Yes/No" answer to "Would you undertake chemistry on this compound if it were a hit?" Only about 30% of the list got a "Yes" vote, and the reasons for rejecting the others were mostly "Too complex", followed closely by "Too simple". (That last one really makes me wonder - doesn't AZ have a big fragment-based drug design effort?) Note also that this sort of experiment has been done before.
Applying their model, the mean score for the "Yes" compounds was 0.67 (s.d.0.16), and the mean score for the "No" compounds was 0.49 (s.d. 0.23, which they say was statistically significant, although that must have been a close call. Overall, I wouldn't say that this test has an especially strong correlation with medicinal chemists' ideas of structural attractiveness, but then, I'm not so sure of the usefulness of those ideas to start with. I think that the two ends of the scale are hard to argue with, but there's a great mass of compounds in the middle that people decide that they like or don't like, without being able to back up those statements with much data. (I'm as guilty as anyone here).
The last part of the paper tries to extend the model from hit compounds to the targets that they bind to - a druggability assessment. The authors looked through the ChEMBL database, and ranked the various target by the scores of the ligands that are associated with them. They found that their mean ligand score for all the targets in there is 0.478. For the targets of approved drugs, it's 0.492, and for the orally active ones it's 0.539 - so there seems to be a trend, although if those differences reached statistical significance, it isn't stated in the paper.
So overall, I find nothing really wrong with this paper, but nothing spectacularly right with it, either. I'd be interested in hearing other calls on it as it gets out into the community. . .
As a follow-up to that post on open offices (and the others referenced in it), I've had a letter from a reader who wonders the following:
(1) How many recent research buildings have been built with open offices, as opposed to cubicles or actual office space? Is this the wave-of-the-future, or is it just a few high-profile examples getting attention?
(2) Does anyone know of any examples where a research department has tried an open-office plan and moved back from it after the experience?
Just to clarify, I don't mean large, relatively open lab spaces (those are pretty common, and often seem to work just fine). What's in question are the wide-open no-walls office and desk areas, with the extreme being the ones where no one has any actual assigned space at all. Thoughts?
SOLITUDE is out of fashion. Our companies, our schools and our culture are in thrall to an idea I call the New Groupthink, which holds that creativity and achievement come from an oddly gregarious place. Most of us now work in teams, in offices without walls, for managers who prize people skills above all. Lone geniuses are out. Collaboration is in.
But there’s a problem with this view. Research strongly suggests that people are more creative when they enjoy privacy and freedom from interruption. And the most spectacularly creative people in many fields are often introverted, according to studies by the psychologists Mihaly Csikszentmihalyi and Gregory Feist. They’re extroverted enough to exchange and advance ideas, but see themselves as independent and individualistic. They’re not joiners by nature.
Well, I wish that I could describe myself as "spectacularly creative", but the rest of that last sentence sounds pretty much like me, anyway. I have no problem talking with people when I meet them. I speak up at meetings, and I really enjoy giving talks to audiences. At the same time. I find that my best thinking is done very much alone. Once I've got something worked out in my head, I'm fine with roaming up and down the halls telling people about it and hearing the reaction. But that working-out has to be done in silence. The phone rings, and my thoughts all take off like like a flock of pigeons. Getting to settle back into their assigned places is not the work of a moment.
For all I know, the new book addresses this problem, but we really need a wider spectrum of words other than "introvert" and "extrovert". There are people who absolutely need human company, human noises and chatter around them. Others would rather have a bit of that, but feel it can be overdone, or just need it in defined amounts, like a meal. And some people don't mind much one way or another, while others are irritated or even panicked by it. You can sort people out, in similar fashion, by their responses to solitude and silence. Given that any research organization is going to have a variety of types in it, you'd think that there would need to be some places where the quiet types could hang out, just as there should be some where the gregarious ones can find what they need.
Let's see here. . .145 messages in the work e-mail queue, but most of them are automated reminders that reminded me of the same thing every day of the break. Now to the lab bench. . .now, that was a good idea, making sure that everything was labeled before leaving. As I've said here before, too many times you come back to a bunch of stuff that you were just sure that you're remember every detail of, and feel like a moron as you look at the label on the vial or flask: "Second batch". "Mostly clean". "Large run". Fascinating! Large run of what, exactly? I have, in years past, been reduced to running NMR and LC/MS on my own reactions just to try to figure out what they were, and that's not right.
Reagents that I'd ordered back before the break have come in, and I do recall why I ordered them, at least. You don't want to put in a request for anything sensitive in late December, though, not if it's going to sit out on your bench at RT for a week or ten days. I'm glad I'm not a cell-culture person or a rodent-raiser; my stuff doesn't need to be fed, washed, or watered, and I have the luxury of just walking away from it.
Big pile of junk on the desk, though, some of which never should have stopped there on its way to the recycling bin. I saved this for this morning, since I thought clearing things off would be a good way to jump-start my brain into work mode again. It's different now than it used to be, though - paper's more ephemeral. I have the PDFs of these papers stored, so the hard copy's just a convenience, and if I can't figure out what use it is by looking it it, into the bin it goes without a worry. In the days of paper files, I had to spend a bit more time wondering if I'd regret tossing something that was hard to obtain and actually useful. No more: if it looks useless or unrecognizable, into the blue bin it goes.
And then, for those of us in industry, the company starts waking up. Meeting invitations begin to arrive, to fill out the new year's calendar. Looking at your own schedule, you see the first repeating meetings from last year starting to show up, although some of these will get canceled because there's nothing to talk about yet. People who wanted something from you back in December will start to remember what it was, at about the same time that you remember the people that you wanted something from.
Time, shortly, for the first reaction, the first LC/MS trace, the first NMR, the first lab assay result of the new year. And for some of us, the first blog post. Welcome back!
For those of you keeping count of how many elements you've used in your chemical careers, you now have another possibility. This paper suggests that uranyl anions are good for epoxide polymerization, so who knows, they may be good for something else as well. I don't anticipate adding this one to my life list, but there's at least a chance of it now. . .
Here's an interesting exercise carried out in the medicinal chemistry departments at J&J. The computational folks took all the molecules in the company's files, and then all the commercially available ones (over five million compounds), minus natural products, which were saved for another effort, and minus the obviously-nondruglike stuff (multiple nitro groups, solid hydrocarbons with no functionality, acid chlorides, etc.) They then clustered things down into (merely!) about 20,000 similarity clusters, and asked the chemists to rate them with up, down, or neutral votes.
What they found was that the opinions of the med-chem staff seemed to match known drug-like properties very closely. Molecular weights in the 300 to 400 range were most favorably received, while the likelihood of a downvote increased below 250 or above 425 or so. Similar trends held for rotatable bonds, hydrogen bond donors and acceptors, clogP, and other classic physical property descriptors. Even the ones that are hard to eyeball, like polar surface area, fell into line.
It's worth asking if that's a good thing, a bad thing, or nothing surprising at all. The authors themselves waffle a bit on that point:
The results of our experiment are fully consistent with prior literature on what confers drug- or lead-like characteristics to a chemical substance. Whether the strategy will yield the desired results in the long term with respect to quality, novelty, and number of hits/leads remains to be seen. It is also unclear whether this strategy can lead to sufficient differentiation from a competitive stand-point. In the meantime, the only undeniable benefits we can point to is that we harnessed our chemists’ opinions to select lead-like molecules that are totally within reasonable property ranges, that fill diversity holes, and that have been purchased for screening, and that we did so in a way that promoted greater transparency, greater awareness, greater collaboration, and a renewed sense of involvement and engagement of our employees.
I'll certainly give them the diversity-of-the-screening-deck point. But I'm not so sure about that renewed sense of involvement stuff. Apparently 145 chemists participated in total (this effort was open to everyone), but no mention is made of what fraction of the total staff that might be. People were advised to try to vote on at least 2,000 clusters (!), but fewer than half the participants even made it that far. Ten people made it halfway through the lot, and 6 lunatics actually voted on every single one of the 22,015 clusters, which makes me think that they had way too much time on their hands and/or have interesting and unusual personality features. A colleague's reaction to that figure was "Wow, they'll have to track those people down", to which my uncharitable reply was "Yeah, with a net".
So while this paper is interesting to read, I can't say that I would have been all that happy participating in it (although I've certainly had smaller-scale experiences of this type). And I'd like to know what the authors thought when they finally assembled all the votes and realized that they'd recapitulated a set of filters that they could have run in a few seconds, since they're surely already built into their software. And we all should reflect on how thoroughly we seem to have incorporated Lipinski's rules into our own software, between our ears. On balance, it's probably a good thing, but it's not without a price.
Talking about hydrogenation here the other day brought up another thought: there's a point where lab work becomes quite difficult, and there are not a lot of good options to help with that. I'm talking about scale-up work, the grey zone between benchtop synthesis and production.
The first of those is where I spend my time. I've often said that there are really only two yields to be calculated in medicinal chemistry: enough and not enough. For some cases, "enough" can be two milligrams, if all you need is one assay (although you're not adding to the screening collection that way). Twenty is plenty for a new compound; it'll be in stock for years at the usual rates of screening.
But later on, when you start to get interested in a particular molecule, those numbers inflate quickly. In vivo tests, PK, toxicology - all these can start to chew up much larger amounts of compound. Hundreds of mgs, then grams, tens of grams, hundreds of grams to get through preclinical because it turns out that you need another large-animal run - those of you in the labs will be familiar with the progression. And well downstream of people like me, there's pilot plant work and real commercial production, where things are measured in kilos and up.
Those folks have a tricky job, but they have one advantage: they know what compound they're making, and eventually they've settled on a route that works. (If you can't do that, well, you don't have a drug). And for a real money-making compound, it's worth investing in dedicated equipment, whole dedicated facilities if need be, just to make it correctly. Earlier in the process, though, you have to be ready for all kinds of chemistries to make all kinds of compounds.
The medium-scale is where those two worlds collide. A medicinal chemist can generally make things up to the tens of grams, maybe a hundred or two, using roughly the same techniques that are used on the smaller scale: round-bottom flasks, suction filtration, magnetic stirring, standard-sized rotary evaporators, silica gel columns. Everything gets bigger and more unwieldy, and it always takes more time (and more solvent) than you thought, but it can get done. Some of the more exotic small-scale chemistries do start to break down on you, which also also adds to the time needed when you have to come up with alternatives.
But if you're always having to work on roughly the hundred-gram scale, you're straddling two regimes. The size of the glassware gets hard to manage - things are heavy, they tip over, they crack - and you really have to have more serious capacity for things like solvent evaporation. But this is way too small for industrial-plant equipment, the kind of thing where you design the process to start on the third floor to take advantage of gravity as you pump the contents of the big batch reactor downstairs for the next step. And it's getting too big for scaled-up versions of standard equipment, but at the same time, you need the versatility that general-purpose labware provides.
Some kinds of gear help to bridge this gap - overhead mechanical stirrers, outboard circulating chillers, and large-capacity rota-vaps come to mind. But there are many other cases where something that's neither benchtop nor pilot plant is needed, and doesn't necessarily exist. Hydrogenation is a case in point. It's done on an industrial scale; that's where all that partially hydrogenated vegetable oil comes from, for one thing. And hydrogenation is common on the gram scale or below. But hydrogenating three hundred grams of something can be a real pain in many labs. The common solution is roll-your-eyes-and-split-it-into-batches, but that gets old fast. . .
We organic chemists have always liked the hydrogenation reaction. Take your compound up in a solvent, add a pinch of black catalyst powder, and put some hydrogen gas into the vessel. Come back a few hours later, filter off the catalyst, and there's your cleanly reduced compound, ready for the next step, often looking even better than it did before you ran the reaction.
For many decades, the standard ways to run these reactions have been to either take a balloon of hydrogen gas and attach it to the top of your round-bottom flask (as in this video clip), or run it on a "Parr shaker". That last piece of equipment has been with us, essentially unchanged, since the 1920s. It's simplicity itself: a thick-walled glass bottle for your reaction, a tube and stopper running into it (with a framework to hold it down under pressure), a hydrogen reservoir, and a motor to shake the bottle around. Its relentless dackadackadackadacka noise is one of the standard sounds of organic chemistry. These things are always off in separate hydrogenation rooms, and when you have several of them running in there at once the out-of-phase clatter makes sequential thought almost impossible. I wish that there were an audio file I could link to, but working organic chemists will all know the tune.
There are newer ways to run the reaction, and flow chemistry is the obvious choice. The "H-Cube" was an early entry into this space, and many of them are to be found around the chemistry world. Unfortunately, many of them are also found gathering dust. Uptake of the machine has been uneven, despite some obvious advantages. That's because the first-generation machine has some obvious disadvantages, too: you have to change the catalyst cartridge every time you want to try something different, because there's only one at a time. The cartridges themselves are not too large, so if your reaction isn't efficient enough, you can have a problem with not being able to run everything in one-time-through mode. And there's no liquid handling - you have to load your sample and collect it in whatever means you see fit. Various people have modified the machine over the years to get around these limitations, and the company now sells a machine incorporating many of these ideas. And there are competitors out there as well.
So here's my question for the chemical audience: has anyone had enough nerve to ditch the Parr shakers completely? I've heard of places that have done it, but when you inquire closely, you often find that there are still a couple around that do a disproportionate share of the hydrogenations. Are there any flow solutions that work well enough to get away with this? You'd think that there would be advantages to a walk-up instrument, if it were robust enough - put your starting solution in position A-3 on the rack, tell it what pressure and temperature you want, which catalyst to use, and add your run to the queue. Come back after lunch and there it is, eluted into another container, ready for you to pick up. NMR machines work this way, and so do microwave reactors. But do hydrogenators? Today, in the real world? Experiences with such things welcome in the comments. . .
I wanted to send people to this 50-year retrospective in J. Med. Chem.. It's one of those looks through the literature, trying to see what kinds of compounds have actually been produced by medicinal chemists. The proxy for that set is all the compounds that have appeared in J. Med. Chem. during that time, all 415, 284 of them.
The idea is to survey the field from a longer perspective than some of the other papers in this vein, and from a wider perspective than the papers that have looked at marketed drugs or structures reported as being in the clinic. I'm reproducing the plot for the molecular weights of the compounds, since it's an important measure and representative of one of the trends that shows up. The prominent line is the plot of mean values, and a blue square shows that the mean for that period was statistically different than the 5-year period before it (it's red if it wasn't). The lower dashed line is the median. The dotted line, however, is the mean for actual launched drugs in each period with a grey band for the 95% confidence interval around it.
As a whole, the mean molecular weight of a J. Med. Chem. has gone up by 25% over the 50-year period, with the steeped increase coming in 1990-1994. "Why, that was the golden age of combichem", some of you might be saying, and so it was. Since that period, though, molecular weights have just increased a small amount, and may now be leveling off. Several other measures show similar trends.
Some interesting variations show up: calculated logP, for example, was just sort of bouncing around until 1985 or so. Then from 1990 on, it started a steep increase, and it's hard to tell if that's leveling off or not even now. At any rate, the clogP of the literature compounds has been higher than that of the launched drugs since the mid-1980s. Another point of interest is the fraction of the molecules with tetrahedral carbons. What you find is that "flatness" in the literature compounds held steady until the early 1990s (by which point it was already disconnected from the launched drugs), but since then it's gotten even worse (and further away from the set of actual drugs). This, as the authors speculate, is surely due to metal-catalyzed couplings taking over the world - you can see the effect right in front of you, and so far, the end is not in sight.
Those two measures are the ones moving the most outside the range of marketed drugs. And despite my shot at early combichem molecules, it's also clear that publication delays mean that some of these things were already happening even before that technique became fashionable (although it certainly revved up the trends). Actually, if you want to know When It Changed in medicinal chemistry, you have to go earlier:
It is worth noting that these trends seemed to accelerate in the mid-1980s, indicating that some change took place in the early 1980s. The most likely explanations for an upward change in the early 1980s (before the age of combinatorial chemistry or high-throughput screening) seem to be advances in molecular biology, i.e., understanding of receptor subtypes leading to concerns about speciﬁcity; target-focused drug design and its corresponding one-property-at-a-time optimization paradigm (possibly exacerbated by structural biology); and improvements in technologies which enabled the synthesis and characterization of more complex molecules.
Target-based drug design, again. I'm really starting to wonder about this whole era. And if you'd told me back in, say, 1991 about these doubts that I'd be having, I'd have been completely dumbfounded. But boy, do I ever have them now. . .
Well, actually, this might not be an anomaly. Medicinal chemists will have heard of the "magic methyl" effect, where small changes can make a big difference in affinity for a drug candidate. This morning I heard an interesting talk by Phil Sanderson of Merck on allosteric Akt inhibitors for cancer. I won't go into all the kinase-ness, although it was definitely worth hearing about. What caught my eye was something he mentioned at the end of the talk. The first compound below was an early screening hit in their work, something that had been in Merck's files since the early 1970s. After a huge amount of work over many years, which you can follow though the literature if you like with a search for "allosteric" and "Akt", they found that four-membered rings were very useful in the structures. Going back to the original structure and adding that same modification to it improved its potency by roughly 100-fold.
One methylene group! You wonder what might have happened if they'd done that early in the project, but as Sanderson correctly noted, no one would have done that (it's synthetically tricky; no one would have put in the time). And they don't have any structural information that seems to explain this effect, he says. So if you're looking for an illustration of what makes medicinal chemistry the wild ride it is, you've got an excellent one here.
I've been in the lab all afternoon setting up reactions, and that prompts me to write about something that I've been noticing. Is it just me, or does Aldrich seem to be abandoning the practice of putting any useful information on their labels?
This has been creeping up for a while, but I worry that instead of an anomaly it's the way of the future. I just got in several bottles of reagents from Aldrich, and basically all they have on their labels are the names of the compounds. No molecular weight, no density, no melting or boiling point: nothing but a line of type surrounded by an Aldrich label. And while I can go look these things up, and while my electronic notebook often is able to provide the information, it would still be a lot more convenient to have it on the label as well. You know, like it used to be.
I assume that this is a cost savings. As a rule, I assume that the most likely answer to any question that starts out "I wonder how come they. . ." is "money". But it's a shame.
A conversation the other day got me to thinking: over the course of my career, I've worked in the following therapeutic areas (more or less in chronological order): CNS (dementia, then Alzheimer's), diabetes, osteoporosis, obesity, oncology, anti-bacterials, multiple sclerosis, and antivirals. That covers a fair amount of ground, but there are still areas I've never really touched on - not much that would qualify as cardiovascular and not much inflammation, for example. So I'm sure that there are readers out there who have seen more drug discovery territory than I have - anyone who thinks that they have the local record, feel free to leave details in the comments.
A second question is whether there are therapeutic areas that you'd always wanted to try but never have. (Anti-infectives would have been in that category for me until the last few years). The opposite of that is well worth asking, too: are there disease areas that you regret ever having touched on? For my part, I learned a lot doing my Alzheimer's work, but in retrospect, much of it was a ferocious waste of effort, considering the results, so I'd probably put that one at the top. Other candidates?
I was talking with some colleagues about underused synthetic chemistry technologies the other day, and one that came up was high pressure. Here's a new paper from JACS looking at pressure effects on a common reaction (Michael addition), and there are quite a few others like it scattered around the literature. In general, reactions that have a lot of steric congestion, or whose transition state occupies less volume than the starting complex, will show some effects as you go to higher pressure.
But no one ever does it. Well, not quite "no one", but pretty damned few people do. I think the problem is that you need special equipment, for the most part, and you also need to have the idea of using high pressure. Both of those are in short supply. But I wonder if someone were to make a lab-friendly high pressure reactor, if it might get taken up a bit more. (Note to equipment manufacturers: I am not promising to buy the thing if you make it. But it's a thought).
A colleague of mine is running a Diels-Alder reaction this morning, and turned out to have never run one before, despite many years of experience in chemistry. (I'd bet, though, that a fair number of chemists who have run the reaction did it in an undergraduate lab and never have since). I've run them - although it's been a while - and I've done the Claisen rearrangement (ditto), the Knoevenagel condensation, the Barbier reaction, and the Henry reaction. I've done plenty of Horner-Emmons-Wadsworth reactions (although not in the last few years), Jones oxidation, Birch reduction, the Arbuzov reaction, and a Chichibabin pyridine synthesis, many years ago. And I've done a Cannizzaro, the Gabriel synthesis, Ferrier rearrangements, the Shapiro reaction, Peterson olefination, and Lindlar reduction. I've run Sandmeyer reactions, the Prins, Staudinger reduction, Ullmann coupling, and Weinreb ketone synthesis. I've done the Wolff–Kishner reduction (once) and Wurtz coupling (once), a Dakin-West (once), a Darzens (once), and a Delepine reaction (once).
But I've never done a straight aldol condensation, at least, not on purpose. And I've never, as far as I can recall, actually done a Fischer indole synthesis, or the lovely Skraup reaction. I've never run a Bayliss-Hillman, a Ritter reaction, a Cope rearrangement, a Julia olefination, a Pictet-Spengler, a Nazarov cyclization, nor a pinacol, and I don't think I've ever set up an ene reaction.
So what's on your list? What's the most famous reaction you've never run? Is there some reaction you've always sort of wanted to do, but never had the reason?
Interesting post from Milkshake over at Org Prep Daily on solvents that don't get used as much as they might in synthetic chemistry. Among them: trifluoroethanol, methyl t-butyl ether, and 1-methoxy-2-propanol. Definitely worth a look for those of us who are trying to get things to work at the bench - other nominations welcomed in the comments.
And if you're looking for someone to do that, I believe that Milkshake himself is still looking for a position (unpaid advertisement!)
OK, here's how I understand the way that medicinal chemistry now works at Pfizer. This system has been coming on for quite a while now, and I don't know if it's been fully rolled out in every therapeutic area yet, but this seems to be The Future According to Groton:
Most compounds, and most actual chemistry bench work, is apparently going to be done at WuXi (or perhaps other contract houses?) Back here in the US, there will be a small group of experienced medicinal chemists at the bench, who will presumably be doing the stuff that can't be easily shipped out (time-critical, difficult chemistry, perhaps even IP-critical stuff, one wonders?) But these people are not, as far as I can tell, supposed to have ideas of their own.
No, ideas are for the Drug Designers, which is where the rest of Pfizer's remaining medicinal chemistry head count are to be found. These are the people who keep trac of the SAR, decided what needs to be made next, and tell the folks in China to make it. It's presumably their call, what to send away for and what to do in-house, but one gets the sense that they're strongly encouraged to ship as much stuff out as possible. Cheaper that way, right? And it's not like there's a whole lot of stateside capacity, anyway, at this point.
What if someone working in the lab has (against all odds) their own thoughts about where the chemistry should go next? I presume that they're going to have to go and consult a Drug Designer, thereby to get the official laying-on of hands. That process will probably work smoothly in some cases, but not so smoothly in others, depending on the personalities involved.
So we have one group of chemists that are supposed to be all hands and no head, and one group that's supposed to be all head and no hands. And although that seems to me to be carrying specialization one crucial step too far, well, it apparently doesn't seem that way to Pfizer's management, and they're putting a lot of money down on their convictions.
And what about the whole WuXi/China angle? The bench chemists there are certainly used to keeping their heads down and taking orders, for better or worse, so that won't be any different. But running entire projects outsourced can be a tricky business. You can end up in a situation where you feel as if you're in a car that only allows you to move the steering wheel every twenty minutes or so. Ah, a package has arrived, a big bunch of analogs that aren't so relevant any more, but what the heck. And that last order has to be modified, and fast, because we just got the assay numbers back, and the PK of the para substituted series now looks like it's not reproducing. And we're not sure if that nitrogen at the other end really needs to be modified any more at this point, but that's the chemistry that works, and we need to keep people busy over there, so another series of reductive aminations it is. . .
That's how I'm picturing it, anyway. It doesn't seem like a particularly attractive (or particularly efficient) picture to me, but it will at least appear to spend less money. What comes out the other end, though, we won't know for a few years. And who knows, someone may have changed their mind by then, anyway. . .
Here's a general question for all you lab types, prompted by some rearranging that I've been doing over at my bench: what piece of equipment do you get the least use out of for the space it takes up? Those dusty items that haven't been touched in a couple of years are obvious candidates, but feel free to add some instruments that work, but crowd out other useful items. . .
I had to use some potassium permanganate a little while back - first time in years I'd had any of it out in the lab, and I was reminded of just what a spectacular purple color the stuff has.
There's some of it dissolving in water, via Flickr, and it's hard to beat for sheer purplelosity. But the solid doesn't look as impressive; it's quite dark (which is probably how it makes such an intense color on dissolution). So what's the best purple solid in the lab?
That's a pretty good shot, but it really should be experienced in person. The stuff is metallic purple flakes, weirdly reflective - it looks like it should be the color of a custom racer's hood, rather than anything you'd actually order from a chemical supply house. Now all I have to do is find a use for it in the lab. . .
Chemists who don't (or don't yet) work in drug discovery often wonder just what sort of chemistry we do over here. There are a lot of jokes about methyl-ethyl-butyl-futile, which have a bit of an edge to them for people just coming out of a big-deal total synthesis group in academia. They wonder if they're really setting themselves up for a yawn-inducing lab career of Suzuki couplings and amide formation, gradually becoming leery of anything that takes more than three steps to make.
Well, now there's some hard data on that topic. The authors took the combined publication output from their company, Pfizer, and GSK, as published in the Journal of Medicinal Chemistry, Bioorganic Med Chem Letters and Bioorganic and Medicinal Chemistry, starting in 2008. And they analyzed this set for what kinds of reactions were used, how long the synthetic routes were, and what kinds of compounds were produced. Their motivation?
. . .discussions with other chemists have revealed that many of our drug discovery colleagues outside the synthetic community perceive our syntheses to consist of typically six steps, predominantly composed of amine deprotections to facilitate amide formation reactions and Suzuki couplings to produce biaryl derivatives. These “typical” syntheses invariably result in large, ﬂat, achiral derivatives destined for screening cascades. We believed these statements to be misconceptions, or at the very least exaggerations, but noted there was little if any hard evidence in the literature to support our case.
Six steps? You must really want those compounds, eh? At any rate, their data set ended up with about 7300 reactions and about 3600 compounds. And some clear trends showed up. For example, nearly half the reactions involved forming carbon-heteroatom bonds, with half of those (22% of the total) being acylations. mostly amide formation. But only about one tenth of the reactions were C-C bond-forming steps (40% of those were Suzuki-style couplings and 18% were Sonogoshira reactions). One-fifth were protecting group manipulations (almost entirely on COOH and amine groups), and eight per cent were heterocycle formation, and everything else was well down into the single digits.
There are some interesting trends in those other reactions, though. Reduction reactions are much more common than oxidations - the frequency of nitro-to-amine reductions is one factor behind that, followed by other groups down to amines (few of these are typically run in the other direction). Among those oxidations, alcohol-to-aldehyde is the favorite. Outside of changes in reduction state, alcohol-to-halide is the single most favorite functional group transformation, followed by acid to acid chloride, both of which make sense from their reactivity in later steps.
Overall, the single biggest reaction is. . .N-acylation to an amide. So that part of the stereotype is true. At the bottom of the list, with only one reaction apiece, were N-alkylation of an aniline, benzylic/allylic oxidation, and alkene oxidation. Sulfonation, nitration, and the Heck reaction were just barely represented as well.
Analyzing the compounds instead of the reactions, they found that 99% of the compounds contained at least one aromatic ring (with almost 40% showing an aryl-aryl linkage) and over half have an amide, which totals aren't going to do much to dispel the stereotypes, either. The most popular heteroaromatic ring is pyridine, followed by pyrimidine and then the most popular of the five-membered ones, pyrazole. 43% have an aliphatic amine, which I can well believe (in fact, I'm surprised that it's not even higher). Most of those are tertiary amines, and the most-represented of those are pyrrolidines, followed closely by piperazines.
In other functionality, about a third of the compounds have at least one fluorine atom in them, and 30% have an aryl chloride. In contrast to the amides, there are only about 10% of the compounds with sulfonamides. 35% have an aryl ether (mostly methoxy), 10% have an aliphatic alcohol (versus only 5% with a phenol). The least-represented functional groups (of the ones that show up at all!) are carbonate, sulfoxide, alkyl chloride, and aryl nitro, followed by amidines and thiols. There's not a single alkyl bromide or aliphatic nitro in the bunch.
The last part of the paper looks at synthetic complexity. About 3000 of the compounds were part of traceable synthetic schemes, and most of these were 3 and 4 steps long. (The distribution has a pretty long tail, though, going out past 10 steps). Molecular weights tend to peak at between 350 and 550, and clogP peaks at around 3.5 to 5. These all sound pretty plausible to me.
Now that we've got a reasonable med-chem snapshot, though, what does it tell us? I'm going to use a whole different post to go into that, but I think that my take-away was that, for the most part, we have a pretty accurate mental picture of the sorts of compounds we make. But is that a good picture, or not?
Well, I've been traveling this week, but have found a bit of time to blog. Today we have something new about SAR, courtesy of the BASF marketing department.
Medicinal chemists are all familiar with the "magic methyl group" effect - the phenomenon of a single methyl sending a compound over the top in terms of activity, selectivity, PK, or what have you. I've seen it several times myself. Usually you starting wondering why you didn't just put the thing in six months before, but that's rarely the way things work out.
Well, we're not the only people who notice such things. Check out this ag-chem ad from BASF for their Kixor herbicide (sent along by an alert reader). Scroll down to the bottom of the page, and you'll find:
Methyl groups serve as "metabolic handles" in crops delivering crop safety and giving you confidence knowing you have made the right choice"
There you have it! Methyl groups add confidence! Now that's worth knowing - and you have to wonder what secrets other functional groups hold. Do carboxylic acids put a spring in your step? Do para-fluoros freshen the breath? Will a sulfonamide help you make the big sale? Someone in the advertising department might believe it - as Dilbert put it, marketing people even believe marketing surveys, so what's the limit?
Well, this post needs updating. In it I mentioned never running a Prins reaction again since the 1980s, nor any photochemistry, and today what do I find myself doing? Both of them, although not at the same time.
I am, fortunately, not running the Prins this way. But even bringing it up at all recalls to me a key part of my education. When I first joined my graduate school research group, I was put to making some tetrahydropyran systems. I was handed a synthesis, drawn up before my arrival, of how to make the first one, and like most first-year grad students, I gamely dug and and started to work on it.
I should have devoted a bit more thought to it. I won't go into the details, but it was a steppy route that relied, in the final ring-closure step, on getting the cyclic ether to form where one of the partners was a neopentyl center. The organic chemists in the audience will immediately be able to guess just how well that went.
So I beat on it and whacked at it, getting nowhere as I used up my starting material, until I was finally driven to the library. In the spring of 1984, that was a different exercise than it is now, involving the 5-year Chemical Abstracts indices and an awful lot of page flipping. (I haven't so much as touched a bound volume of CA in I don't know how many years now). If you were a nomenclature whiz, you could try looking up your compound, or something like it, in the name index, but a higher-percentage move was often to look up the empirical formula. That gave you a better shot, because (if it was there at all) you could see how CA named your system and work from there.
To my great surprise, the second set of collective indices I checked (the good ol' 9th), yielded a direct hit on an empirical formula, and the name looked like exactly what I had been trying to make. The reference was in Tetrahedron, which we most certainly had on the shelf, and I zipped over to see if there was any detail on how to make the stuff.
There was indeed. A one-stepper Prins cyclization gave just the ring system I'd been trying to make, and that was one step from the intermediate I needed. I just stared at the page, though. I honestly couldn't believe that this was real (as I mentioned, I was in about my second month of grad school lab work). Surely the synthesis I'd been given was the way to make this stuff? Surely the people responsible for it had checked the literature before drawing it up? (After all, it had only taken my a few minutes to find the stuff myself). Surely I couldn't just make the ring in one afternoon using two starting materials I could buy cheaply from Aldrich?
Well, surely I could. And that's just what I did, and got my project moving along until the next interesting difficulty came up a couple of months later. But I still recall standing there in the Duke chemistry library, looking at that journal article "with a wild surmise" that perhaps I should check things out for myself next time instead of just taking everyone else's word. It took a couple more lessons for me to really grasp that principle (Nullius in verba!, but it's helped me out a great deal over the years. I have the 27-year-old photocopy I made that afternoon in front of me now. It's a good reminder.
Here's a question for all the organic chemists out there. A discussion with some colleagues the other day got me to thinking about the reactions that we all tend to underuse. The category I offered up was gaseous reagents. Outside of hydrogenation, I think that many of us sort of go "Ehh. . ." when we come across transformations that need lecture bottles, cylinder, regulators, and so on.
Add to that the unpleasant nature of many of the gases themselves, and it's easier to find something else to do. But there are a lot of good reactions and reagents in this category - metal-catalyzed CO insertions, reactions with ammonia, acetylene, sulfur dioxide, etc. There's just a bit of a higher activation barrier to getting around to running them.
I'd say that photochemistry and electrochemistry are in this "rather do something else" category as well. Other nominations welcome!
For the chemists out there in the crowd: have you been looking for a paper to read that's filled, beginning to end, with good, solid, old-fashioned medicinal chemistry? Look no further than this one, on recent reports of isosteres. This sort of thing is still the heat of med-chem as it's practiced in the real world - messing around with the structure of an active molecule to see what you can improve and what you can get away with.
If you're not a medicinal chemist, the idea of a bioisostere is some chemical group that can substitute for another one. Classic examples are things like swapping in a tetrazole ring for a carboxylic acid or an oxadiazole for an ester. Here are some examples - even if your organic chemistry is shaky, you can see the similarities across these structures. If it works, you can change the other properties of your molecule (solubility, stability, selectivity) for the better while still keeping the key features that made the original group valuable for activity. It's not something that just automatically comes through every time - sometimes there just is no substitute - but it works enough of the time to be one of the essential techniques.
Management fads are truly a bad sign. I don't think that there's anyone out there in the working world who doesn't realize this, on some level, but it's worth keeping in mind. When some higher-up at your company decides "You know, we'd make a huge leap in productivity if we just did everything totally differently than we've ever done them before - I read this great article!", then you really need to hunker down until the fit passes.
Well, some of the folks at GlaxoSmithKline down in Research Triangle are probably looking for somewhere to hide. Because according to this article, the company is (yes!) at the forefront of a movement that's (yes!) sweeping the nation: open office space. No assigned desks, no permanent locations, just everyone floating around in a cloud of happy productivity. Jim Edwards at Bnet is right when he calls this "slightly insane".
Um. . .haven't we been hearing about this wonderful innovation for years now? And haven't several companies tried it and abandoned it, because (strangely enough) their employees didn't like the idea of putting their possessions into lockers every morning, wandering (or scrambling) around for desk space, and being unable to leave the slightest sign of anything personal around their work area? Here are some tempting details:
All employees are assigned a storage unit where they can keep files, a keyboard, a power pack and a mouse. There will also be group storage spaces where files that need to be accessed by more than one person can be kept. Any files that are not accessed regularly will be stored off-site. GSK's document retention policy isn't changing; it just may end up being followed more closely.
Gosh, that does sound like what I've been yearning for all these years. Making the transition to this wonderful environment isn't easy, though:
The larger move will ultimately include an extensive education campaign to prepare employees for their new surroundings.
Employees will work in neighborhoods, each of which includes meeting rooms and quiet areas. They'll attend etiquette workshops, and each neighborhood will adopt a set of policies to deal with hypothetical situations that may come up.
The groups that are moving to the new layout are those whose managers embraced the change. (Admin Shelby) Bryant now sits at a desk directly across from her boss, David Bishop, GSK's director of site operations in RTP.
Bishop said as the move gets closer, more and more departments are expressing interest in unchaining themselves from their desk.
"I don't believe we will ever get to where everybody wants it," he said.
Maybe not! But that'll be their loss, won't it, not having to go through all that education, and attend those etiquette workshops, and then throw out all their stuff. Honestly, I think I'd rather chew on glass than attend a series of workplace etiquette seminars and get re-educated by someone who tells me that I'm not going to have a desk any more. And those meetings to set behavior policies, those will be delightfully excruciating, for sure. What on earth is the company thinking?
Well, they're thinking about how this will allow them to vacate several buildings, because housing the employees this way takes up less room. So once again, this conforms to a rule that has seldom let me down: any question that starts out with "I wonder how come they. . ." can be answered with the word "Money".
Here's a problem that I've seen at every company I've worked at, and there are good reasons to believe that it afflicts every company out there. That's because I think it's grounded in human nature: dog-and-pony-itis.
That's the phrase I use for what happens to meetings over time. Many readers will be familiar with the process: a company gradually accumulates regular meetings on its internal calendar - project team meetings, individual chemistry and biology meetings inside that, overall review meetings, resourcing, planning, interdisciplinary meetings. . .everyone who's anyone, in some companies, has to be calling a meeting of their very own.
Eventually, someone says "Enough!" and purges the schedule, replacing the tangle of overlapping meetings with A Brand New Meeting or two. These will actually discuss issues, for once, and people are encouraged to actually say what's really going on with their projects. For once. And who knows, maybe that's the case (for once) - but it doesn't last.
Because every time, in my experience, the Brand New Meeting itself starts to collect barnacles. Over time, it becomes less useful, and more of a show. The music starts up, the Pomeranian dogs start hopping around and barking, and the trained horses make their entrance from the wings. It becomes more expedient to just get up and tell people the broad strokes of a project, especially the broad strokes that are actually working, and leave the messy details out. And gradually, other meetings spring up to try to take up the slack, since nothing ever seems to get done at the Brand New. . .
The thing is, I don't know how to stop this from happening. It comes on like rust. I've lost count of the we've-got-to-get-rid-of-this-stupid-meeting initiatives I've seen over the years, and every time the cycles eventually repeats. So here's a question: has anyone broken out? And if you have, how? Suggestions welcomed in the comments. . .
One of the comments to this post brought my attention to this paper in JACS on a new fluorinating agent. I just finished writing a column on fluorinated drugs for Chemistry World, so the subject is on my mind.
I have to say, this looks like it could be a very useful reagent. I've never worked with any arylsulfur trifluorides, but that looks to change soon, since I'd guess that this stuff will shortly be commercialized. An air-stable, non-runaway reactive fluorinating reagent would hit the spot. It would be fine with me if I never open another bottle of DAST again, and my experiences with the likes of xenon difluoride haven't been wonderful, either. If anyone gets a chance to try this compound out, let us know if it's all it's billed to be!
Here's a lab equipment question that someone probably knows the answer to, but that someone isn't me. Anyone know where you can buy Corex glass? I'm looking for a tube of the stuff, about 3cm by 28cm, but the only thing I can find are centrifuge tubes. The stuff is (or at least was) made by Corning. It's an aluminosilicate and it's mechanically quite strong, so the centrifuge use makes sense, but no one seems to sell a plain tube of the stuff. Any ideas?
Here's a look (PDF) at the Novartis "Labs of the Future". This looks like another one of these "open lab" concepts, and it appears that Basel has really bought into the idea. The interview with the two biologists helping to head the project is. . .well, it's very Swiss, that's the best description. When asked "What indicators would you select to measure improvement?" after people move in, the answer is:
Bouwmeester: That depends on the monitoring period. I am assuming that one or two months after we move into the building, the employees will already be experiencing a new dynamic. If they report a positive difference, that will be a first measure of success. It is important that the people in the LOTF develop some
kind of ownership regarding their role in the building. It will be a more active role than usual. The LOTF is basically an open space where you can observe your peers across the hierarchies. This is a different type of social architecture compared to 10 years ago, or even today still. Everybody will be more under observation and observing more than before. The dynamism of the interaction between people will increase. The employees themselves will have to decide what is common practice on their floor. Of course the concept will need to be adapted over time; I would be surprised
if all concepts materialize exactly as anticipated.
I would be, too. In fact, I'd like to propose that last sentence be printed up on T-shirts, coffee mugs, and posters, but that's probably not going to happen. More on what this is actually going to look like:
Korthäuer: (There will be) big screens, placed where people typically pass by. There will be video cameras installed on each laptop, allowing easy and informal contacts. The information technology concept is an important part of it. We have also designed special furniture that serves the same goal. We want to get rid of functional cells such as coffee rooms, writing rooms, lab rooms etc. Our aim is to bring the walls down. But of course we still need differentiation. In the LOTF
there are still compartmentalized areas with particular qualities, constructed according to people’s needs and workflow requirements. . .
Korthäuer: On the information technology side, we are trying to implement a few applications which really support the concept. There will be videoconferences, ‘smart’ whiteboards that allow notes to be captured electronically. We focus on proven technologies. Gradually, we will bring new technologies into the building such as haptic interfaces. Removing the walls in a building can bring about big changes. There will be much less storage room. Therefore, a little robot operating in an elevator shaft will transport materials ordered by laptop up from the basement to the floors. . .
Bouwmeester: We have already implemented Virtual Reality Rooms with ultra-high-resolution video screens, so that the quality is as though you were in a real-life meeting; the effect is quite spectacular. As with any global project, it will all require a certain attitude, a set of skills that people will have to develop. Much energy and time will be needed to communicate efficiently between places as different as Basel, Cambridge and Shanghai. . .
Allow me to note a few difficulties. For one, those high-res video conference venues still have to deal with switching and transmission delays, especially across the distances that the Novartis guys are talking about. So if you try to have a spirited real-time discussion, you'll mostly be getting very clear, sharp, high-fidelity views of people interrupting each other and pausing awkwardly. (Update: see the comments section - some users are reporting more successful experience.) I have a more macro-scale worry about this sort of thing, too, having to do with my suspicion of plans that depend on people finally shaping up and acting the way that they're supposed to. As with any global project, y'know.
I think that I'll let Tom Wolfe have the last word here, since what he wrote in From Bauhaus to Our House is still applicable, over thirty years later:
I once saw the owners of such a place driven to the edge of sensory deprivation by the whiteness & lightness & leanness & cleanness & bareness & spareness of it all. They became desperate for an antidote, such as coziness & color. They tried to bury the obligatory white sofas under Thai-silk throw pillows of every rebellious, iridescent shade of magenta, pink, and tropical green imaginable. But the architect returned, as he always does, like the conscience of a Calvinist, and he lectured them and hectored them and chucked the shimmering little sweet things out.
Every great law firm in New York moves without a sputter of protest into a glass-box office building with concrete slab floors and seven-foot-ten-inch-high concrete slab ceilings and plasterboard walls and pygmy corridors. . .Without a peep they move in!—even though the glass box appalls them all. . .
I find the relation of the architect to the client in America today wonderfully eccentric, bordering on the perverse. . .after 1945 our plutocrats, bureaucrats, board chairmen, CEO's, commissioners, and college presidents undergo an inexplicable change. They become diffident and reticent. All at once they are willing to accept that glass of ice water in the face, that bracing slap across the mouth, that reprimand for the fat on one's bourgeois soul, known as modern architecture.
And why? They can't tell you. They look up at the barefaced buildings they have bought, those great hulking structures they hate so thoroughly, and they can't figure it out themselves. It makes their heads hurt.
From reader Jose, in the comments thread to the most recent post:
"Published I find it ironic that so many pharma sites who hired hotshot architects to design labspaces that foster as much personal interaction as possible, are now pumping the virtues of collaborations across 10 time zones."
Medicinal chemists spend an awful lot of time working with SAR, structure-activity relationship(s). That's how we think: hmm, what happens if I put a chloro there? If I make that ring one size larger? If I flip that stereocenter/add a nitrogen/tie back that chain? Ideally, you pick up on a trend that you can exploit to give you a better compound, but the problem is, no SAR trend lasts forever. Methyl's good, ethyl's fine, anything bigger falls off the cliff - that sort of thing.
Activity "cliffs" of this sort are the subject of a paper earlier this year in the Journal of Chemical Information and Modeling. (For some earlier approaches to this same type of question, see here, here, here, and especially here).This group (from Germany) looked over several public SAR databases and used a new algorithm to extract "matched molecular pairs", which are compounds that differ only at one point in their structure. And what they were looking for wasn't the orderly progressions; they were after the changes that tended to suddenly change the activity of a compound by at least 100-fold. Were there, they wondered, functional group shifts that have a greater or lesser chance of doing that, over a wide range of targets and compound classes?
It looks like there are, and they're the transformations that you might well imagine. Messing around with a carboxyl group, for example, seems rarely to be a neutral event. Carboxylates are so relentlessly polar and hydrogen-bonding that your SAR is probably going to love 'em or hate 'em. The next two liveliest groups were carbonyls (in general) and amines. Of less interest (but equally believable) is the transformation from methyl to bulky alkyl (or vice versa, which is the direction I'd recommend people try to go if at all possible - other things being equal, no one should grease up their compounds unless there's absolutely no choice).
Well, it needs no ghost come from the grave to tell us this, either. How about any surprises? Adding a secondary hydroxyl group was surprisingly silent, compared to what you might picture. And switching from secondary to tertiary amines (just with methyl groups) is a much less conservative switch than you might imagine, with several huge activity shifts across different target classes. Introduction of methyl ethers rarely affected things much one way or another, and that might account for the low tendency of dimethylamine-to-morpholine doing anything. Small halogens on aryl rings (fluorine, chlorine) had low potential to cause big shifts, with ortho-chloros showing no examples of that happening at all. Oddly (at least to me) was the fact that morpholine-to-alkylpiperazine showed almost no big changes, either.
But it has to be emphasized that these are (1) averages and (2) averages over a large (but not gigantic) data set. For example, one of the "no changes at all" transformations is a favorite med-chem isostere, thiophene for phenyl. And that's true - most of the time, that does nothing. But I've seen two examples in my career when that one actually caused a big change in activity, so it's rare, but not impossible. That's the thing that makes med-chem so enjoyable and so frustrating at the same time. It's full of things (like actually discovering a drug) that are rare, but not quite impossible.
I'm enjoying myself very much in the lab today, doing something I haven't done in 20 years: photochemistry. I did some during my post-doc (with Bernd Giese, which is also the last time I've done free radical chemistry, at least on purpose). Since then, though, it's one of those things that's never come up. We had a mercury lamp apparatus in my grad school group, which I saw used a few times - one of which resulted in one of those nose-wrinkling "What's that funny smell?" moments, when the person running it forgot to turn on the cooling water. Don't do that. Medium-pressure mercury lamps can get pretty toasty. (They'll also permanently tan your eyeballs if you're so foolish as to look at them, I should also note, so don't do that, either!)
Most synthetic chemists will have had a brief experience with the technique - it's very appealing to think of doing chemistry just by shining a light on the reaction. But there can be a lot of variables - the sort of lamp you use (and thus the wavelengths and energy flux), various filters, sensitizing additives, hardware setups. Many people find that they use it for one reaction at some point, to make a specific compound, and never quite find a use for it again. In my experience, every decent-sized chemistry department has a photochemical rig of some sort, and no one quite knows where all its parts are.
That's probably a shame. There are a lot of unusual and interesting reactions that can be done photochemically - if you like 3- and 4-membered rings, this is certainly a field you should look into. I can recommend this recent bookas a general review of the field, for anyone who's thinking about it. We'll see how much use I get out of my current setup, but for now, I'm happily blasting away with the ultraviolet. . .
Update: blasting away is right! My cooling water dribbled down and then cut out on me after I tried to turn it down a bit, and, well. . . now I'm cleaning melted goo off of the quartz. A razor blade is working pretty well, but that's no way to treat a working piece of equipment.
Earlier this year, I wrote here about using calorimetry in drug discovery. Years ago, people would have given you the raised eyebrow if you'd suggested that, but it's gradually becoming more popular, especially among people doing fragment-based drug discovery. After all, the binding energy that we depend on for our drug candidates is a thermodynamic property, and you can detect the heat being given off when the molecules bind well. Calorimetry also lets you break that binding energy down into its enthalpic (delta-H) and entropic (T delta-S) components, which is hard to do by other means.
And there's where the arguing starts. As I mentioned back in March, one idea that's been floating around is that better drug molecules tend to have more of an enthalpic contribution to their binding. Very roughly speaking, enthalpic interactions are often what med-chemists call "positive" ones like forming a new hydrogen bond or pi-stack, whereas entropic interactions are often just due to pushing water molecules off the protein with some greasy part of your molecule. (Note: there are several tricky double-back-around exceptions to both of those mental models. Thermodynamics is a resourceful field!) But in that way, it makes sense that more robust compounds with better properties might well be more enthalpically-driven in their binding.
But we do not live in a world bounded by what makes intuitive sense. Some people think that the examples given in the literature for this effect are the only decent examples that anyone has. At the fragment conference I attended the other week, though, a speaker from Astex (a company that's certainly run a lot of fragment optimization projects) said that they're basically not seeing it. In their hands, some lead series are enthalpy-driven as they get better, some are entropy-driven, and some switch gears as the SAR evolves. Another speaker said that they, on the other hand, do tend to go with the enthalpy-driven compounds, but I'm not sure if that's just because they don't have as much data as the Astex people do.
So as far as I'm concerned, the whole concept that I talked about in March is still in the "interesting but unproven" category. We're all looking for new ways to pick better starting compounds or optimize leads, but I'm still not sure if this is going to do the trick. . .
I had an email this morning asking me to settle a bet on lab technique. I'm not sure I know the answer myself, so I figured I'd throw the question out to the readership.
So here goes: in your vacuum cold trap, which I'll assume is cooled by dry ice (and not liquid nitrogen, for the most part), what solvent do you use: acetone or isopropanol? (If you use something else, feel free to add it to the list, but I think you'll be in a distinct minority). As for me, I used acetone back in grad school, but switched over to isopropanol years ago, because I didn't have to change it (or add to it) so often.
Mat Todd of the University of Sydney looks over the SciFoo conference that we both attended during the summer, and contrasts that to an ACS meeting. The comparison isn't kind, as you'd imagine:
. . .with a few very notable exceptions the talks I saw were a) presented in a dull Powerpoint-heavy series of slides with verbal commentary about what was on the slides where even the presenter was visibly bored with what they were saying and b) on published material that was c) way too predictable and incremental. So both the presentational style and the content were disappointing. So many talks at the ACS would have been more interesting if the speaker had simply given out paper copies of their latest paper and given us 10 minutes to read it in silence then 10 minutes to talk about it. Now of course specialism necessitates incrementalism in content, but it’s no good if the meeting becomes a chore to sit and listen to. Nor is it good if the talks come out of the Powerpoint Machine (the genius of the “Chicken Talk” is that you can kind of follow the talk structure without listening to the content – it sounds exactly like most academic talks right up to the last supplementary slide in response to the second question at the end). In maybe 80% of the talks I attended nobody asked questions, or nobody was allowed to, or people asked “pity questions” just to break the awkward silence, but which were in no way interesting in themselves.
"A chore" is exactly what I find too many presentations and conferences to be, unfortunately. If we limited presentations, as Mat suggests, to people who are excited about their results, we'd have a lot of short meetings in this field. . .
Here's something that you don't think about until you actually work in a department full of chemists: how do you keep track of who's got what, and where it is? Everyone has reagents on their bench, and hidden away under the fume hood, and they're ordering more (and using up the current bottles) all the time. And people are wandering from lab to lab, borrowing and pilfering, sometimes when the original owners are there, and sometimes not. So how do you know what you have?
I've seen a number of approaches to this chemical inventory problem. The essential thing is that every bottle of every reagent be trackable. That means some sort of bar-coding system, most likely. Those bar codes need to go on when the compounds come in the door, ideally, so there aren't a lot of invisible reagents floating around. I think the best way to do this is to have the shipping and receiving people involved - if you trust the chemists to bar-code things, many of them just won't quite get around to it.
The next big question is whether you're going to have a centralized chemical stockroom or not (I've worked under both systems). The stockroom probably makes it easier to keep track of things, in general, since otherwise the available reagents are distributed throughout the labs at all times (instead of the ten per cent or so that are actually in active use). And it helps to have some place to send all those bottles back to - when you clean up your bench, you know that there's one thing you can do immediately, which helps keep the chemicals homing back to the central location.
A stockroom, though, requires dedicated space and dedicated head count, and neither of those are always feasible. The spread-throughout-the-labs approach puts the work back on the chemists. Its biggest disadvantage is entropy: bottles move around, get silently consumed, or get just plain lost. (That happens with a stockroom system, too, but at a slower rate). After a while, your map of the chemical inventory is useless - and for popular reagents, "a while" might be about two weeks.
That brings up the moving-chemicals problem, and to be honest, I've never seen a good solution to that one. Ideally, any time a person borrows some reagent from its known location, they scan the bar code so the system knows that it's moved. In practice, you know, you're just using it for a couple of days. Or you're just running one reaction, and you're going to take it right back. It's just right down the hall; the folks down there know where it is. Right. A stockroom system keeps this from randomizing things as quickly, but no matter what, this sort of Brownian motion is going to scramble things eventually.
So there has to be a regular inventory taken, no matter whose system you're using. Whether that's someone from the stockroom coming through and scanning all the benches and cabinets, or whether you declare Inventory Day and make all the chemists do it themselves, it has to be done. Twice a year is not too often, in my experience.
If anyone has solutions to some of these problems that I haven't touched on, feel free to share them in the comments. But please, no "Just Make Everyone Act Responsibly For Once" recommendations. Let's assume that people are intrinsically looking for the easy ways out, and work from that - it's a worldview that has never disappointed me.
This year's Nobel for palladium-catalyzed coupling reactions highlighted how useful these have become. But what every practicing organic chemist knows is how complicated they can be, particularly when you first couple of favorite recipes don't work. I've long thought that almost any metal-catalyzed transformation can be optimized, if you're just willing to devote enough of your life to it. But you have to have a good reason to wade into the swamp, because there sure are a lot of variables that can be tweaked. Here's a good case in point, recently published in Organic Letters. A perfectly reasonable reaction (C-H arylation of a chloropyrazole, which had been demonstrated before) was run through the statistical wringer to track down the best conditions.
They looked at 6 solvents, 10 bases, 4 catalysts, 5 ligands, and 4 additives, which would give you 7200 combinations if you ran the whole shebang. A Design of Experiments approach cut the number of actual runs down significantly, and then (fortunately) some of the variables turned out to be pretty insensitive. So this one wasn't as bad as some of them get - the ligand didn't seem to have too much effect, for example, whereas in some other Pd couplings it's crucial. (The choice of base had a much bigger effect, in case you're wondering). Their best set of conditions seems to work reasonably well across a range of possible substrates.
DoE is worth a post of its own, and that'll be a timely thing for me. After brushing up against it for years, I may finally have a use for the technique soon. For those who don't know it, it's basically a way to figure out how to most efficiently sample "experiment space", by getting the most information out of each different run. And then you use principal components analysis (or something similar) to see what the most important changes were, and how they correlate to each other. It's asking, mathematically, what a synthetic chemist wants to know about a complicated reaction recipe: what changes are responsible for most of the variation in the results, and how can I track them down by running a reasonable number of experiments? In the drug industry, process chemists think about this sort of thing a lot more than discovery chemists do, but it's worth keeping an eye out for any time the approach could be helpful.
Update: here's a trip report on this conference over at Practical Fragments
I'm back from Philadelphia and the FBLD conference. I'm not going to put a trip report up on the blog - although I'm certainly writing one up for my colleagues at work - but a number of people at the meeting asked me what I might say about it here.
Well, I enjoyed it. I tend to like more focused conferences like this one, anyway, where most of the people doing the best work in a field can attend what's still a fairly small meeting. It probably helps that this isn't a very old series of meetings, too. Over time, some sort of scientific entropy sets in, and the topics covered can begin to smear out a bit. Some of the longer-running Gordon Conferences are (to me, anyway) a little blurry about what they're trying to cover.
That same tendency can affect individual talks. We medicinal chemists are particularly guilty of that, since our discipline spreads over a pretty wide area. At a meeting like this one, which was all about fragment-based techniques, people had to resist the temptation to keep going past the fragment-based parts of their talk. Once you get up toward 400 molecular weight, you're not talking about fragments any more - you're doing good old medicinal chemistry. Maybe it's structure-based at that point, maybe not, and maybe you're using some of the biophysical techniques that help out with moving fragment leads forward - but the fragment techniques are what got you to that point, not what's carrying you forward through the concerns about PK, formulations, polymorphs, and all the other later-stage worries of a drug program.
The speakers at this meeting generally did a good job avoiding this pitfall, but I have to admit that the few times I saw PK data come up on the screen, I stopped taking notes. I didn't stop listening, on the chance that there might be something interesting, but it certainly wasn't what I was there to focus on. One could imagine a whole meeting about solving PK problems in drug development - there probably is one, actually. But at that one, you'd have to make sure that the speakers didn't spend time telling you about the neat fragment-based techniques that led to their drug candidate.
As I said, though, there were a lot of interesting speakers at this one, and not a single talk was anything close to a complete waste of time. How many meetings can you say that about? Things ran smoothly, and with notably better food than some of the other conferences I've attended. Some meetings just pitch a bunch of Wissenschaftlerfutter out onto the tables, figuring that people will deal with it - and to be honest, they're usually right. We'll eat most anything in this field, although I've been told that physicists are even less discriminating, so at least we have that.
A group at GSK has published a paper in Angewandte Chemie on the kinds of reactions that medicinal chemists use, and why they use them. The conclusions will come as no surprise to anyone practicing in the field. The workhorse reactions were condensations (amides, etc.), palladium-catalyzed couplings, and alkylations. And if you look at the reactions used to generate arrays (small libraries) of compounds simultaneously, those reactions almost take over the list.
Why is that? Well, for one thing, because those reactions tend to work. You'll almost always get product out of them - no small thing. You really, really don't want to spend time tweaking a reaction just to make it produce something, not when the odds of any individual product working are still small. And you can also get a good amount of structural diversity off-the-shelf, by using the huge numbers of commercial amines, acids, aryl boronic acids, and so on. They're also fast reactions, for the most part: set 'em up one day, work 'em up the next, and on to the next analogs.
The authors list some criteria that new reactions would need to order to make the list: not fussy about conditions (temperature, time, order of addition, atmosphere, etc.), compatible with polar solvents, tolerant of a wide range of functional groups, easy to dispense, easy to clean up, and so on. They mention that there's been funding in the UK over the last few years (as there has been here) for discovery of new chemistries that would meet this standards, but (reading between the lines) it doesn't seem as if anything major has made it up the charts yet.
Their other take-home is that people who specialize in running arrays can usually do them more efficiently than those who set them up just once in a while. They suggest that it takes a slightly different sort of person to be good at this:
. . . Owing to their focus on and expertise with arrays, we have found that the array chemists can make, purify, analyze, and register array compounds more efficiently than the program medicinal chemists. They are frequently also more effective in delivering a higher percentage of products from the array in greater yield and purity.
The team has a unique skill set and mindset. We have found that an array chemist should be highly organized, show attention to detail, be manually dexterous, be comfortable with repeatedly delivering to deadlines, and have an ability to work with often introverted and occasionally obstreperous program chemists ! This combination of characteristics is uncommon amongst chemists.
As an obstreperous program chemist myself, I should resent that remark. But you know, they're probably right. . .
A comment to the most recent post on puns mentioned the famous JOC paper in verse from the 1970s, and prompted another comment that "If you have to report your results as a villanelle, I think we'll see fewer methyl, ethyl, butyl, futile papers. . ."
Well, it's not a whole paper, for sure. But here's the best that I can do in thirty minutes:
Put In Another Methyl Group: A Villanelle
I shouldn't have to put a methyl there
No matter what the modeling group might say
So it docks to perfection: I don't care.
The project head gave me an evil glare
When I spoke up at our review today.
I shouldn't have to put a methyl there.
"The glutamate will pick up that lone pair".
Who knows? That might be right; I couldn't say.
So it docks to perfection: I don't care.
How do these really bind? We don't know where.
It's not like we can get a good X-ray.
I shouldn't have to put a methyl there.
Quaternary chiral centers? I don't dare.
I'd need two months if I needed a day.
So it docks to perfection: I don't care.
But no one ever said research was fair.
I'm going to have to come up with a way.
I shouldn't have to put a methyl there.
So it docks to perfection: I don't care.
Update: yes, I'm going to give the molecular modelers their own poem. It's only fair!
I had an interesting email about a 2009 paper in Drug Discovery Today that has some bearing on the "how much compound to submit" question, as well as several other areas. It's from a team at AstraZeneca, and covers their application of "Lean Six Sigma" to the drug discovery process. I didn't see it at the time, but The title probably made me skip over it even if I had.
I'll admit my biases up front: outside of its possible uses in sheer widget-production-line settings, I've tended to regard Six Sigma and its variants as a buzzword-driven cult. From what I've been able to see of it, it generates a huge number of meetings and exhortations from management, along with a blizzard of posters, slogans, and other detritus. On the other hand, it gives everyone responsible a feeling that they've Really Accomplished Something, which is what most of these managerial overhauls seem to deliver before - or in place of - anything concrete. There, I feel better already.
On the other hand, I am presumably a scientist, so I should be willing to be persuaded by evidence. And if sensible recommendations emerge, I probably shouldn't be so steamed up about the process used to arrive at them. So, what are the changes that the AZ team says that they made?
Well, first off is a realization that too much time was being spent early on in resynthesis. The group ended up recommending that every lead-optimization compound be submitted in at least a 30 to 35 mg batch. From my experience, that's definitely on the high side; a lot of people don't seem to produce that much. But according to the AZ people, it really does save you time in the long run.
A more controversial shift was in the way that chemistry teams work. Reflecting on the relationship between overall speed and the amount of work in progress, they came up with this:
Traditionally, chemists have worked alongside each other, each working on multiple target compounds independently from the other members in the team. Unless managed very carefully by the team leader, this model results in a large, and relatively invisible, amount of work in progress across a team of chemists. In order to reduce the lead time for each target, it was decided to introduce more cooperative team working, combined with actively restricting the work in progress. The key driver to achieve and sustain these two goals was the introduction of a visual planning system that enables control of work in progress and also facil-
itates work sharing across the team. Such a visual planning system also allows the team to keep track of ideas, arrival of starting materials, ongoing synthesis and compounds being puriﬁed. It also makes problems more readily recognizable when they do occur.
We have reﬂected on why chemistry teams have always been organized in such an individual-based way. We believe that a major factor lies in the education and training of chemists at universities, in particular at the doctoral and postdoctoral level, which is always focused on delivery of separate pieces of work by the students. This habit has then been maintained in the pharmaceutical industry even though team working, with chemists supporting each other in the delivery of compounds, would be beneﬁcial and reduce synthesis lead times.
OK, that by itself is enough to run a big discussion here, so I think I'll split off the rest of the AZ ideas into another post or two. So, what do you think? Is the "You do your compounds and I'll do mine" style hurting productivity in drug research? Is the switch to something else desirable, or even possible? And if it is, has AstraZeneca really accomplished it, or do they just say that they have? (Nothing personal intended there - it's just that I've seen a lot of "Now we do everything differently!" presentations over the years. . .) After all, this paper is over a year old now, and presumably covers things that happened well before that. Is this how things really work at AZ? Let the discussion commence!
Talking about the amounts of compound to submit as a medicinal chemist brings up another topic. In every med-chem department I've worked in, there have been periodic exhortations for the chemists to register their intermediates. But too few people do.
For those outside the field, what I'm referring to are the "stepping stone" compounds along the way to structures that you're actually targeting. We try not to have these pathways go on too long, but there are often compounds that lack a key methyl group, or don't have the right stuff on the nitrogen yet, and so on. From the way that the compounds in a project have been running, you can be pretty sure that these things aren't going to be of much use for your current biological target - but the point is that they could be useful for someone else.
I've always been surprised by how many compounds sit on the benches, or in drawers, and never quite make it into the compound repository. To be sure, there are plenty of intermediates that shouldn't go in there - anyone who compound-codes a red-hot acid chloride should be whacked over the head. But plenty of things that people think of as "just starting material" or "just an intermediate" have nothing wrong with them, and should be added. I don't even mind a Boc group on an amine - t-butyl's not anyone's favorite, but there are plenty of drugs out there with carbamates on them. Fmoc is where I'd draw the line, though, since I think there's too much of a possibility for the binding to be driving by that big ol' fluorenyl, which is the first thing you'd want to get rid of if the compound hits. I don't think I'd go for any silyl groups on the alcohols, but benzyls and the like are fine.
So do a good deed today if you're in the lab: clear out a few of those compounds you have sitting around and put numbers on 'em. In your heart, you know it's the right thing to do!
Here's a question for those of you out in the industry: how much compound do you make, when you make a new one? Sometimes this question is equivalent to asking "How little will they let you get away with?" Different organizations have different requirements, on paper and for real, as to what that amount is. Five mg? Ten?
I've worked with people who kept coding these little 1.5mg amounts on most of their compounds, but I only do that if I'm desperate. That's really only going to do the immediate project any good, and not much, at that, if you want to do anything beyond the first in vitro assays. You'd like to have something living in the screening files so it can perhaps do some good later on. I try to aim for 10 to 20mg of compound, myself, although I don't always make it. And you?
Here's a lab question for everyone. I have a bottle of Aldrich copper oxide nanopowder on my lab bench; I've been meaning to try it out for some Ullmann reactions. I note that Aldrich (and others) are now selling a variety of such nanopowders, mostly metals and insoluble metal compounds.
And that makes sense, because these are the things that tend to react at their surfaces, and you'd have to think that a real nanopowder would have a tremendous surface area. My question is: does this really work out? Has anyone noticed a difference between the nanopowder form of a particular reagent and its more traditional one? I can imagine there being one - but I can also imagine the particles clumping up under some conditions and giving you back the equivalent of the cheaper stuff, too. Any hands-on experience out there?
One of the folks over at Chemistry Blog has run into a shortage: he and his labmates have tried to order (-) sparteine from every supplier in the book, and there's none to be had. So if anyone has a big dusty bottle of it sitting around, you might drop these desperate chemists a line. But that got me thinking about the way things suddenly dry up like this.
The situation is different than for an industrial chemical shortage, like the acetonitrile crunch that we went through a while back (and which has long since eased up). It's quite unusual for a bulk chemical like that to go down; several factors hit all at once in that case, and it affected an awful lot of people who needed the solvent. But fine chemicals are much weirder. When you trace some of them back to their real sources, you sometimes find that there are really only a couple of people in the world at any given time making some of these things. Or, in many cases, you find that there's no one making it at all - someone made a bunch a few years ago for some reason, sold the excess to a supplier, and everyone else has been buying it from that same bottle ever since.
So when one of these small-scale itemsevaporates, the reason can be supply: no one makes it any more. Or it can be demand-driven: a single drug company's scale-up group can deplete the world's commercial supply of some strange little molecule when they suddenly switch to a 500-gram run. Everyone working in such a group knows to call all the suppliers when they have a prep calling for some weirdo starting material, and they'll often take the precaution of ordering whatever's out there to be had. (That serves as a cushion while they contract someone else to crank out a batch or figure out how to make it themselves). Naturally, you'd rather have your drug candidates depend only on things that can be ordered in tank car lots, but that's just not always possible.
So it could be that someone needed a lot of (-) sparteine for an asymmetric synthesis recently, and bought up the existing world stocks. But this one sounds like more of a supply problem. There would appear to be customers out there, who have been draining the existing stocks, but no one's been able to replenish them. TCI apparently stated that it's the starting material for (-) sparteine that has become unavailable, but that sounds a bit funny, since it would surprise me if the material on the market is synthetic. Sparteine is a naturally occurring alkaloid, found in several species of plant, and it's very hard to compete with isolation of the natural product in those cases.
Perhaps TCI means that the usual plant source is unavailable - that's happened before, too. A spike in Tamiflu demand a few years ago suddenly sent the price of star anise up to record levels, since the chiral starting material (shikimic acid) in the usual synthesis was most conveniently isolated from that source. But for sparteine, it looks as if the isolation comes from plants in the broom family, which are not exactly rare shrubs, so I'm not sure what's going on. Any ideas?
As a brief followup to my "Elements I Have Yet to Use" post, I note this new paper on cleavage of molecular nitrogen by a hafnium complex. And to get right down to organic synthesis, here's a paper from last year that used hafnium triflate as a Lewis acid.
OK, here goes: has anyone out there ever used hafnium for anything? Anything at all? I sure haven't. (N.b. - ordering some on purpose to raise your desktop monitor or prop the door open does not count).
In keeping with the problem discussed here ("sticky containers"), there's a report that a lot of common spectrometric DNA assays may have been affected by leaching of various absorbing contaminants from plastic labware. If the published work is shown relative to control tubes, things should be (roughly) OK, but if not, well. . .who knows? Especially if the experiments were done using the less expensive tubes, which seem to be more prone to emitting gunk.
We take containers for granted in most lab situations, but we really shouldn't. Everything - all the plastics, all the types of glass, all the metals - is capable of causing trouble under some conditions. And it tends to sneak up on us when it happens. (Of course, there are more, well, noticeable problems with plastics in the organic chemistry lab, but that's another story. Watch out for the flying cork rings!)
For the medicinal chemists in the audience, I wanted to strongly recommend a new paper from a group at Roche. It's a tour through the various sorts of interactions between proteins and ligands, with copious examples, and it's a very sensible look at the subject. It covers a number of topics that have been discussed here (and throughout the literature in recent years), and looks to be an excellent one-stop reference.
In fact, read the right way, it's a testament to how tricky medicinal chemistry is. Some of the topics are hydrogen bonds (and why they can be excellent keys to binding or, alternatively, of no use whatsoever), water molecules bound to proteins (and why disturbing them can account for large amounts of binding energy, or, alternatively, kill your compound's chances of ever binding at all), halogen bonds (which really do exist, although not everyone realizes that), interactions with aryl rings (some of which can be just as beneficial coming in 90 degrees to where you might imagine), and so on.
And this is just to get compounds to bind to their targets, which is the absolute first step on the road to a drug. Then you can start worrying about how to have your compounds not bind to things you don't want (many of which you probably don't even realize even are out there). And about how to get it to decent blood levels, for a decent amount of time, and into the right compartments of the body. And at that point, it's nearly time to see if it does any good for the disease you're trying to target!
The discussion of "privileged scaffolds" in drugs here the other day got me to thinking. A colleague of mine mentioned that there may well be structures that don't hit nearly as often as you'd think. The example that came to his mind was homopiperazine, and he might have a point; I've never had much luck with those myself. That's not much of a data set, though, so I wanted to throw the question out for discussion.
We'll have to be careful to account for Commercial Availability Bias (which at least for homopiperazines has decreased over the years) and Synthetic Tractability Bias. Some structures don't show up much because they just don't get made much. And we'll also have to be sure that we're talking about the same things: benzo-fused homopiperazines (and other fused seven-membered rings) hit like crazy, as opposed to the monocyclic ones, which seem to be lower down the scale, somehow.
It's not implausible that there should be underprivileged scaffolds. The variety of binding sites is large, but not infinite, and I'm sure that it follows a power-law distribution like so many other things. The usual tricks (donor-acceptor pairs spaced about so wide apart, pi-stacking sandwiches, salt bridges) surely account for much more than their random share of the total amount of binding stabilization out there in the biosphere. And some structures are going to match up with those motifs better than others.
So, any nominations? Have any of you had structural types that seem as if they should be good, but always underperform?
Update, March 19: I've added a few more suppliers to the list, and broken out a third category for the mixed reviews. And I note in the comments that someone claiming to be Kathy Yu from 3B Chemicals is threatening me with legal action. The IP address resolves only to AT&T Internet Services, but there does appear to be someone from that name who works at 3B. I hope, for her sake and that of the company, that this is someone impersonating her, because whoever is leaving these comments is doing 3B no favors.
And since I am reporting opinions, both my own and those of other contributors that I have no reason to doubt, and am doing so without malicious intent, I will cheerfully ignore all legal threats.
OK, here are the lists of good companies and not-so-good companies, based on my experience and those of readers. I've had some personal communications, too, which I've added to the data set. As more reports come in, this will be the post that's updated, so it can serve as a reference.
I should note up front that I'm not listing the Big Guys, since (while they can have their ups and downs), you generally know that they're going to send you something. What we're looking at are the companies that you might not have dealt with, but want to know if they're reliable. And that brings us to the:
ABCR: good prices and hit rate on orders. Very professional.
Activate: expensive, but what's there is there, and it's the right stuff.
Adesis: not cheap, but very reliable and willing to work with customers to deliver similar compounds.
Advanced Chem Tech: recommended for peptide/amino acid stuff.
AK Scientific: several good reports on availability and purity.
Alinda: have ordered one thing from them, which was fine.
Anaspec: good reports on reliability
Apollo: good stuff, but catalog needs to be a bit more in line with their real stock.
Array: very pricey, but it's all there.
Astatech: good experience reported
Bionet: interesting catalog, doesn't back-order you.
Chembridge: a big catalog, but it's all real. Occasional purity problem.
Chem/Impex: good hit rate on availability. Some questions on their chiral purities.
Combi-Blocks: good list of useful intermediates, delivers on them.
Enamine: similar to ChemBridge in many ways. Big catalog. Not the fastest out there.
Florida Center for Heterocyclics: occasional purity issues, but they do deliver.
Frontier: great source for boronic acids and the like.
Life Chemicals: have had good experiences with compound purity here.
Lu: good source for custom peptides.
Matrix: interesting catalog, which they will really ship to you.
Maybridge: on the border of being one of the big guys. Very reliable.
Midwest: good reports on reliability.
Netchem: custom synthesis, but (for once!) with good turnaround and purity.
Oakwood/Fluorochem: good prices and reliability.
Peptide Protein Research: good for custom peptides.
Pharmacore: good stock of intermediates.
Rieke: reliable, only game in town for many odd reagents.
Strem: well known for quality inorganics and organometallics.
Synquest: used to be PCR. Good customer service.
Synthonix: stuff is in stock, customer service is responsive.
TCI: has always delivered, and quickly.
Transworld: very reliable and responsive.
Tyger: have never had a problem with them.
Waterstone Chemicals: good experience on pricing and availability
American Custom Chemicals (ACC): several tales of bad purity and customer service, but others have had nothing but good experiences with them.
3B Chemicals: "will lead you on for months". Several bad experiences reported. On the other hand, I've just heard directly from a colleague who's had good luck with them.
J&W Pharmlab: bad experience reported (delays and purity), but others OK.
Ontario: one good report, but others complain of availability and leads times.
SPECS: mixed reports, but overall positive.
The Not So Good:
Ambinter: seems to source a lot of stuff from mystery suppliers. Many delays.
Any supplier, sad to say, with "Hangzhou" or "Shanghai" in the name. Tend to have absolutely nothing on the shelf, and if there's even a listed price, it's science fiction.
Anichem: very bad experience here with unexplained delays.
Beta Pharma: bad experience reported.
ChemMaker: very negative report on customer service and responsiveness.
City Chemicals: several bad experiences reported
Combi-Phos: several reports of purity problems.
Rarechem: haven't come across anyone with a good report here.
UK Green: a bad experience reported.
Uorsy: nothing ever seems to be in stock.
Zelinsky: several bad experiences reported.
Is it just me, or is the fine chemicals supply business getting even more out of hand than usual? I was just talking with a colleague who'd sourced an interesting intermediate, at the (steep!) price of about $900 for a gram. She placed the order and. . .you guessed it, the supplier immediately back-ordered it, saying the price had changed. It took someone from Purchasing to drag the new quote out of them (they apparently wouldn't give it over the phone). Now (to no one's surprise, I'm sure) the material is over $3000/gram, and will have a lead time of weeks.
This sort of thing has gone one for a long time, of course. But my impression is that there's more of it than ever. When the Chinese and ex-Soviet suppliers began to appear some years ago, they were often a pretty cheap source of some unusual compounds. But that's changed.
My belief - and I'll be glad to hear from people who do more compound purchasing than I do - is that the Chinese outfits especially have decided in recent years that they have some real pricing power, and are pushing it to see how far they can get. Add that to the hand-waving don't-you-worry-now aspect of many of their product lists, and you have a recipe for irritation and wasted time. (Another colleague described some of these online catalogs as "things they wish they sold".)
A previous comment on to a post like this listed some suppliers that had been found to be reliable, and I'll reproduce that here, in no particular order: Maybridge, Enamine, Asinex, Key Organics, ChemBridge, Specs, ASDI Biosciences, InterBioScreen, Vitas M Labs, Life Chemicals, Labotest, and TimTec. Suppliers of weirdo outlier compounds that nonetheless tend to come through were Albany Molecular, Chem T&I, Florida Center for Heterocyclic Compounds, and Princeton Biomolecular. I've used many of those folks myself (and have had particular success with Life Chemicals and Specs, as far as availability and purity). Some of these companies are faster to ship than others. But the thing that stands out with all of them is that they have what they say that they have, and what's more, it costs what it says that it costs.
For intermediates, as opposed to final-compound-like structures, I'd say that I've had good dealings with Apollo, Synthonix, Matrix, Pharmacore, Adesis, Tyger, Fluorochem, Oakwood, and Astatech. There are, I'm sure, several other suppliers in this category, and I'd be glad to list more of them after seeing the comments.
But now let's reverse the polarity. What's a blog for if you can't say what you really think? Here, then, is a preliminary blacklist of suppliers. These people either have product listings that overlay poorly with reality, try to jerk you around on the price, take much longer to deliver than their initial estimates, or (lucky you) can do all of these at once. My personal recommendation is to be quite careful with ChemPacific, Uorsys, CTI, Zelinsky, and everyone with the words "Hangzhou" or "Shanghai" in the company name.
Please feel free to add others to the lists. I'll do a consolidated post reflecting everyone's experience - that way, we can give business to deserving companies you might not have worked with before, and we can perhaps shame some others into acting more reasonably.
The entries I've done on the "open-plan" Biochemistry building at Oxford (see also Jim Hu) generated a lot of comments from people who've worked in poorly designed science facilities. I've heard from Linda Wang, a reporter at C&E News, who's writing article on this very subject. She's looking for chemists who are willing to talk about both good and bad experiences working in various building designs, so if you fit that description, feel free to email her at l_wang-at-acs.org (email address de-spammified, just substitute the usual symbol) or give her a call at 202-872-4579.
A discussion at work the other day got me to thinking: what structures do you medicinal chemists out there just refuse to work on? Any? We all have our own prejudices - in fact, if you get enough chemists into one conference room, one or another of them will probably rule out just about any structure you propose. Try that sometime, and be sure to sneak a few marketed drugs in there to tick people off. Don't like organoazides? Michael acceptors? Nitroaromatics? Epoxides? Chloromethyl ketones? They're out there working in the real world and making real money.
Now, I'm not saying that you should concentrate on these things. The success rate for (say) chloromethyl ketones is surely lower than for a lot of other compound classes, and there's only so much time and money available. That's why I have personal rules like "No Naphthyls". If someone shows me a structure with a raw naphthalene hanging off it that works, well, good for them, and I guess I'd work on it on that basis. But I won't contribute any myself, because I think the odds are too low.
But I have even more deep-seated prejudices. There are some structures that I just don't think have a chance, even if it looks like they work at first. I'd rather kill them immediately than take the (grave) chance of wasting everyone's time. The first thing I can think of on such a list would be quinones and their ilk. There are just too many other bad things that they're capable of. Now that I've said this, I feel sure that someone is come up in the comments with an example of a quinone that's making five hundred million dollars a year or something. But I sure can't think of one myself, and I just don't see the point of trying to make a drug out of such a structure (unless their lively reactivity is part of some nasty mechanism all its own, in which case, good luck to you).
I've written both here and elsewhere about flow chemistry, the technique where you pump your reactions through a reaction tube of some sort rather than mixing them up in a flask. And I freely admit that I have a fondness for the idea, but it's definitely not the answer to every problem.
For one thing, I tend to like the idea of sending reactants over a bed of catalyst or solid-supported reagent (what I call Type II or Type III flow reactions in that 2008 link above). Type I reactions, in my scheme, are the ones where you just use a plain tube or channel, and all the reactants are present in solution. A big advantage of those, as far as I can tell, is to handle tricky intermediates that you wouldn't want to have large amounts of or to control potential runaway exothermic reactions. There's also the possibility of running the reaction stream through some solid-phase purifications and scavengers, the way Steve Ley and his group like to work, which is convenient since you're already pumping the stuff along anyway.
But the sorts of reactions that you often see in the flow-chemistry equipment brochures. . .well, that's something else again. More than one outfit has earnestly tried to sell me a machine based on how well it did a Fischer esterification. My problem wasn't that the reaction was discovered almost in Neanderthal times - it was that Thag run reaction in round bottom flask, work fine, not need flow reactor. I mean, really, this is a nonexistent problem and needs no solution.
So I read this new paper in Angewandte Chemie with interest. The authors are looking at some standard catalytic organic transformations and comparing them carefully between batch mode and a flow setup. They stipulate at the beginning that flow chemistry has the advantages mentioned above, but they're wondering about what it can do for more ordinary chemistry:
"In addition to these developments, general and rather sweeping claims have been made that microreactor systems accelerate organic reactions and that lower catalyst loadings and higher yields can routinely be achieved in these systems compared to those of reactions carried out in flasks. Despite these potential advantages, examples of successful implementation of microflow reaction technologies in either academic organic synthesis or industrial process research and manufacturing remain more isolated than these reports would suggest. However, the implication is that it is only a matter of time before microflow reactors will dominate laboratory studies aimed at both fundamental research and practical applications of complex organic reactions, with our current mode of operation in reaction flasks ultimately becoming a relic of the past. It seems therefore worthwhile to examine the assumptions behind this viewpoint to provide a critical analysis of “flask versus flow” as a means for effecting reactions."
What they find is that there's very little difference. A catalyzed aldol reaction that was studied under flow conditions by the Seeburger lab is shown to perform identically to a batch reaction, if you make sure to run them at the same temperature and with the same catalyst loading. The paper then looks at asymmetric addition of diethyl zinc to benzaldehyde, a model reaction that I often wish would disappear from human consciousness so it would afflict us no more. But here, too, under more challenging heat-transfer conditions, flow showed no differences from batch. The authors point out that this reaction is, in fact, run under industrial conditions, but not in a flow apparatus. Rather, it's done in batch mode, but though good old slow addition of reagent, which also gives you control over exotherms.
The authors specifically exempt all supported-reagent chemistry from their analysis, so that preserves what I like about flow systems. But for homogeneous reactions, the only time they can see an advantage for the flow reactors is when there's a potential for a dangerous rise in temperature. So now we'll see what some of the more flow-oriented people have to say in reply. . .
Not as much time to blog this morning (and it's been hard getting into the site, since there are a lot of people who apparently want to know how to order some dioxygen difluoride). For one thing, I'm clearing a bunch of reactions out, and I've been devoting thought to how to do that in the laziest possible manner.
Maybe I should clarify that. What I mean is, how do I work up all these reactions quickly, in such a way as to make clean compounds that are worth testing, but spend the least amount of effort doing so? There are, of course, all sorts of brute-force ways to bang these things through, some of which would involve me not leaving my lab for the next three days or so, but I have other demands on my time. It's worth thinking about the most efficient way to do it.
Since these things I'm making all have acidic groups hanging off them, the most appealing idea I have right now is to use a basic resin to clean them up - as most med-chem types know, you can generally stick acidic compounds onto such resin, wash a lot of the crud off and throw that away, then bump your desired compounds off with some sort of acidic wash. This sort of solid-phase cleanup became popular in the combichem era, and has persisted for situations like this.
That's probably how I'll go, as opposed to, say, individually loading every single one of the compounds onto the HPLC machine. That would make me rather unpopular with the other people who might want to use that instrument before March is upon us, for one thing, and it would be complete overkill as well. These compounds are all pretty clean looking - a wash-and-rinse protocol should turn them out in good shape, and there's no need to use Super Ultimate Purification on them. (And besides, I'm making them all in reasonable quantity, which would bog down the HPLC even more).
An even more brainless way to do this workup would be to run every single compound through an automated column (like a Biotage). At least the HPLC has a liquid handler on it - I could set the thing up with a few rows of samples to inject, and walk away with some degree of confidence that it would run them. But the Biotage-type machines are usually one-at-a-time things, for larger samples. One batch of five grams of stuff would be perfect - two or three dozen at 100 mgs each, not so.
And all this makes me think of someone who used to work down the hall from me (no more clues than that!) I noticed that he was always cranking away in the lab, every time I went past. I mean, this guy looked like one of those multi-armed Hindu god statues, with each hand holding a round-bottom flask or a TLC plate. Impressive! Until I realized, after dealing with him a while, that the reason he was zipping around in there like a hamster was because he was doing everything in the most brutal and time-wasting way possible. He seemed to pick his reactions and protocols according to how much hand labor they involved: the more, the better.
I took a vow never to be him, and today I plan to live up to that. Measure twice, cut once and all that.
Here's a quick question for those of you that order a lot of odd little compounds. A correspondent tells me that he's been ordering resupplies from some of the usual suspects in this area (ChemBridge, ChemDiv - you know the sorts of companies, if you're in the med-chem business). And a higher than usual percentage of compounds are coming back as "Unavailable". . .only to show up available, at a significantly higher price, from Aurora.
Now, I certainly don't know the business arrangements between all these companies. I know that some of the compounds themselves are clearly coming from the same original sources, often somewhere in Russia, and make their way into a number of catalogs at once. But is this Aurora business a coincidence. . .or a business model? Anyone seen this happen personally?
Yesterday's post touched on something that all experienced drug discovery people have been through: the compound that works - until a new batch is made. Then it doesn't work so well. What to do?
You have a fork in the road here: one route is labeled "Blame the Assay" and the other one is "Blame the Compound". Neither can be ruled out at first, but the second alternative is easier to check out, thanks to modern analytical chemistry. A clean (or at least identical) LC/MS, a good NMR, even (gasp!) elemental analysis - all these can reassure you that the compound itself hasn't changed.
But sometimes it has. In my experience, the biggest mistake is to not fully characterize the original batch, particularly if it's a purchased compound, or if it comes from the dusty recesses of the archive. You really, really want to do an analytical check on these things. Labels can be mistaken, purity can be overestimated, compounds can decompose. I've seen all of these derail things. I believe I've mentioned a putative phosphatase inhibitor I worked on once, presented to me as a fine lead right out of the screening files. We resynthesized a batch of it, which promptly made the assay collapse. Despite having been told that the original compound had checked out just fine, I sent some out for elemental analysis, and marked some of the lesser-used boxes on the form while I was at it. This showed that the archive compound was, in fact, about a 1:1 zinc complex, for reasons that were lost in the mists of time, and that this (as you can imagine) did have a bit of an effect on the primary enzyme assay.
And I've seen plenty of things that have fallen apart on storage, and several commercial compounds that were clean as could be, but whose identity had no relation to what was on their labels (or their invoices for payment, dang it all). Always check, and always do that first. But what if you have, and the second lot doesn't work, and it appears to match the first in every way?
Personally, I say run the assay again, with whatever controls you can think of. I think at that point the chances of something odd happening there are greater than the chemical alternative, which is the dreaded Infinitely Active Impurity. Several times over the years, people have tried to convince me that even though some compound may look 99% clean, that all the activity is actually down there in the trace contaminants, and that if we just find it, we'll have something that'll be so potent that it'll make our heads spin. A successful conclusion to one of these snipe hunts is theoretically possible. But I have never witnessed one.
I'm willing to credit the flip side argument, the Infinitely Nasty Impurity, a bit more. It's easier to imagine something that would vigorously mess up an assay, although even then you generally need more than a trace. An equimolar amount of zinc will do. But an incredibly active compound, one that does just what you want, but in quantities so small that you've missed seeing it? Unlikely. Look for it, sure, but don't expect to find anything - and have 'em re-run that assay while you're looking.
Update: I meant to mention this, but a comment brings it up as well. One thing that may not show up so easily is a difference in the physical form of the compound, depending on how it's produced. This will mainly show up if you're (for example) dosing a suspension of powdered drug substance in an animal. A solution assay should cancel these things out (in vitro or in vivo), but you need to make sure that everything's really in solution. . .
I am here to confess to a deep-seated prejudice, one that has been with me for many years now. I know that others feel differently, but I'm sticking to my rule: No Naphthyls.
OK, pile on me now for having a closed mind. I know that there are drugs that are more successful than anything I'll ever make that have a naphthalene in them. (At least that structure's a small one). It's just that I see a naphthyl as the worst sort of "potency through greasiness" move in drug design. They hurt your solubility, drive up your molecular weight, open you to metabolites that you may not care for, and all for what? A little activity in your in vitro assay.
I'm getting close to putting cyclohexyl on the same list, if you want to know the truth. Problem is, people make these things "just as SAR compounds". You know, they'll trowel this hunk of grease onto the side of the molecule, just to see what happens, and if it really looks good, well, they'll. . .find some way to make it better. Right. Tetrahydropyranyl instead, that'll do it. But my attitude is, why not just make the THP derivative in the first place, if that's where you're going to go?
SAR is long, and life is short. There isn't time to make everything. So I decided a long time ago that I'd try to only make structures that I could live with. That still admits a lot of weird stuff, don't get me wrong. I have functional groups on my go-to lists that make people roll their eyes. But I draw the line at flat slabs of lard. No naphthalenes.
It's been a busy day on the front lines of science around here; apologies for not getting anything up until now. Here's a topic that I was discussing with some colleagues not too long ago: how much do we need to know about each other's specialties, anyway? I'm assuming that the answer is "more than nothing", although if someone wants to make the zilch case, I'd be interested in hearing it done.
But once past that, what's the optimum? I (for example) have never done cell culture. Nor do I see myself ever needing to do it (and anyone who needs me to is clearly in a bad way). I know the broad outlines of the field, but almost none of the details, and I'm sure that even my broad outlines have some faint parts in them. So if I'm at some sort of meeting where the problem-of-the-day turns on cell culture issues, I can be of no help at all. Is this a problem? I understand that different cells take to culture conditions differently, have varying growth rates, need media changes and whatnot, can generally only be passaged a certain number of times, etc. In short, I know roughly what to expect from my cell culture colleagues, and what would be silly of me to demand. Is that about right?
After all, I don't expect them to know the ins and outs of medicinal chemistry, particularly the synthetic organic lab part of it. Things like methylene chloride being rather more weirdly polar as a solvent than you'd expect, or the fact that some amines will stick to solid magnesium sulfate drying agent (but not sodium sulfate), or how you can azeotrope out acetic acid with toluene, or how you want palladium tetrakis to be lemon yellow and not orange - these and dozens of others are the tricks of my lab trade, and they don't know mine in the same way that I don't know theirs.
But I do like it when my biology colleagues have the broad outlines - that molecules with chiral centers, other things being equal, are often harder to make than achiral structures, that sticking a lot of cycloalkyl grease on a molecule is asking for metabolic trouble (no matter what it does for the potency in the assays), what sorts of things tend to make a molecule more (or less) soluble, and so on. Those are the equivalent of me knowing that primary cell lines lose some of their functions in culture, the difference between transient transfection and a stable cell line, etc.
It seems to me that each discipline in our business could draw up a list of What Everyone Else In the Company Should Know about their area. So, to start off with, I'm throwing the comments section over to what biologists (and others) should know, at a minimum, about med-chem. Take it away!
About a year ago, I wrote here about the impressive-looking new biochemistry building at Oxford, and wondered if it would work out quite the way the architects intended. Now I see a report from a post-doc who actually works there:
My first thoughts setting foot into the new building were the following: How are we supposed to concentrate with our offices in the atrium? How are we going to manage to work at such tiny desks?
I have to say, these initial concerns were justified. We hear the lab phone of every single floor ringing through the atrium, including people's mobile phones (which also causes envy towards those who actually have reception). When people really need to concentrate on writing, reading or thinking while others are discussing their work or are simply chatting, the atmosphere can get pretty tense. And even if it was completely silent in the atrium, the small size of the desks already makes working difficult. . .I once discussed the lack of space with our head of department. He simply replied: when you have to write a paper, you work from home anyway... I'd say £47 million well spent!