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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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: derekb.lowe@gmail.com Twitter: Dereklowe

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June 28, 2013

Hybrid Biomolecules, Edible And Not

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Posted by Derek

While writing up that eight-toxic-foods rebuttal the other day, I started reading up on Olestra, the "fake fat" that made the list. While it has to be considered a failure for its developers, I found the chemistry behind it interesting, and it got me to thinking.

First off, for those outside the chemical/biochemical field, a brief introduction to fat. We (and most other organisms) all store it in pretty much the same way: a backbone of glycerol (three carbons in a row, each with an alcohol), and each alcohol turned into an ester with a fatty acid. Those fatty acids are long carbon-chain compounds with a carboxylic acid group on the end, and when you've combined three of them onto a glycerol (fully loaded, as it were), you have a triglyceride. When the body wants to break that down for use as energy, it cleaves off the fatty acids one at a time (leading to diglycerides and monoglycerides), and the fatty acids are then chewed up two carbons at a time. (They're made two carbons at a time, too, so the ones found in living creatures are very heavily biased towards even-numbered carbon counts).

That intro is enough to make sense of some of the things you'll see in a blood test, like the tryglyceride levels and the free fatty acids. But there are a lot of details hidden in there. For one thing, there's a whole suite of different enzymes that do the work of assembling and breaking down the glycerides, and they're under all sorts of control mechanisms. And while glycerol is glycerol, the fatty acids themselves come in a huge variety - different lengths, presence of single or multiple double bonds up and down the chain (and keep in mind that double bonds in the middle of such a chain come in both cis and trans varieties), etc. So with this long list, glycerides get produced in all kinds of combinations, depending on diet, the tissue involved, and other factors. And beyond that, most all these components, up and down the list, are involved as signaling molecules on various proteins, substrates for other enzymes, starting materials for whole other chemical sequences, etc. Lipidology gets very complicated very quickly, and you may have noticed (via the changing dietary advice over the years) that we don't quite have it figured out yet. Nowhere near.

So what's Olestra? It's nothing more than table sugar (sucrose) with its alcohol groups given the fatty-acid-ester treatment. What you end up with is a molecule that acts very much like normal fats - both of them are polyhydroxy compounds decorated with fatty acids, after all. But the enzymes that cleave the various fatty ester groups don't recognize an esterified sucrose as anything they've seen before, and thus Olestra goes on its way uncleaved and unmetabolized. That, actually, is one of the things that seems to have sunk it in the market. A good-sized dose of Olestra has to go somewhere, namely, right through your digestive tract. The reports of the side effects this could bring on were not a good selling point, although there's a debate about how often they were observed in the real world.

Otherwise, though, it seems to have been a reasonably convincing substitute for actual fats. I've never had any Olestra myself - it would be interesting to see if I could distinguish potato chips made with it from the conventional ones. Procter and Gamble were of the opinion that there was no discernable difference in taste or texture, but I've heard from people who say that they can tell under blinded conditions

Another side effect is that the stuff would tend to dissolve greasier substances and carry them along. Thus the problems with fat-soluble vitamin absorption with Olestra, which was compensated for by adding more of these vitamins (such as A, D, and K) the to potato chips made with it. It should be remembered that potato chips are not a major source of vitamins - well, not for most consumers - but the concern was that a steady diet of Olestra-containing foods could interfere with nutrient absorption from the other foods eaten at the same time. This is purely a greasiness/water solubility issue (logP being the medicinal chemist's measuring scale), and Olestra has also shown an ability to sequester and remove things like ingested PCBs, for the same reasons. It doesn't know a vitamin from anything else; it just knows what it can dissolve.

Olestra spent a lot of time in human testing. Since lipid molecules (as mentioned above) are involved in a lot of different processes, these studies were done to see if there were any signs of Olestra participating in other pathways. Nothing was ever found; the stuff was too odd-looking to the body's enzymes to be digested, and too odd-looking to work its way into these other mechanisms as well. It just sort of made its way through.

But such cross-bred biomolecule hybrids are an interesting class. Just as you don't see fully-esterified sugar molecules in cells, there are many other things like this that don't show up - at least, as far as I know. The carboxylic acids at the C-terminals of amino acids, oligopeptides, and proteins don't get handled in living systems as esters much (or if they do, I've missed it). Imagine glycerol with peptides esterified off the OH groups, for example, in sort of a protein-fat hybrid. Now try it with glucose - I've never seen that, either. In the same way, the OH groups on amino acids like serine are available to be esterified, but that's another class of compounds I don't know much about. Phosphorylation, yes, but not plain esters. It's not like esters are somehow alien to biochemistry - you have the glycerides, for one, and esters of cholesterol are a well-known class of compound. Biochemistry as we know has just never gotten around to using these things.

It's easy to imagine a slightly alien life form using fatty acid esters of the higher sugars as its energy storage class rather than stopping at glycerol. These creatures would have enzymes that would take Olestra apart like a wooden puzzle, and might be baffled at our own molecules. Somewhere, some unusual-looking alien is perhaps proposing glycerol esters as an indigestible substitute for the diet - worried, perhaps, about the way everyone's tentacles are getting so swollen these days, what with the overabundance of cheap food and all, and sensing a market opportunity. Perhaps Zarkon & Yipslarg will succeed where Procter and Gamble failed.

Comments (43) + TrackBacks (0) | Category: Life As We (Don't) Know It

June 27, 2013

Sealed Up And Ready to Go

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Posted by Derek

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.

Comments (42) + TrackBacks (0) | Category: Life in the Drug Labs

June 26, 2013

Protein-Protein Compounds - The Flip Side

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Posted by Derek

The topic of protein-protein inhibitor compounds has come up around here several times. It's the classic "undruggable" target, although that adjective isn't quite accurate. Let's leave it at "definitely harder than the usual stuff"; no one could argue with that.

But there's a flip side to this area that people don't think about so much. What about a compound that would make two proteins interact more tightly? A conversation with a reader of the site got me to thinking about this, and it turns out that there's a good review of the concept here, from 2012. The compounds that are known to really do this sort of thing all seem to be natural products, which I don't suppose should come as a surprise. The most well-worked-out of the group is (as some readers will have guessed) FK506 (tacrolimus). Very few drug research organizations have been brave enough to tackle a mechanism like this, so you're not going to see many examples of synthetic compounds. How small (and drug-like) a compound can be and still work through a mechanism like this is an open question.

In principle, it shouldn't be that hard a screen to run - you could imagine an assay where you watch a FRET signal hang around instead of disappearing (once you're sure that hanging all the FRET thingies off the protein partners didn't mess with the binding event, of course). You'd probably be able to see this effect by biophysical techniques as well - NMR, SPR (if you could recapitulate the protein-protein interaction with an immobilized partner on a chip), etc. You'd want a lot of structural information - seeing some sort of plausible binding surface that spans the two proteins would help to settle the nerves a bit.

You'd also want some targets, but there are probably more of them than we're used to thinking about. That's because we're don't tend to think about this mode of action at all, and if you're not keeping it in mind, you won't spot opportunities for it. The whole gain-of-function side of the business is hard to work in, for good reasons. I'm not aware of endogenous small molecules that work this way, so it's not like there are a lot of highly evolved binding pockets waiting for us to fill them. Come to think of it, I'm not aware of endogenous small molecules that work as protein-protein inhibitors, either - those processes seem to get regulated by modifications on the proteins themselves, by local concentration, or by intervention of still other proteins to rearrange binding surfaces. The scarce evolutionary record of this sort of thing might be an accident, or it might be telling us (believably) that this isn't an easy thing to do.

So I would not necessarily pin all my hopes for next year's new targets portfolio on one of these, but it would be interesting to screen and see what might turn up. Who wants to be first?

Update: here's an example from the recent literature for you!

Comments (27) + TrackBacks (0) | Category: Drug Assays | Natural Products

June 25, 2013

Picking Out Incorrect Natural Products

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Posted by Derek

Once in a while, you see people who've gone to the trouble of synthesizing a natural product, only to find that its structure had been incorrectly assigned. (Back in the days when structure elucidation was much harder, R. B. Woodward had this on his list of reasons to do total synthesis, although it wasn't number one).

Now there might be computational method that could flag incorrect structures earlier. This paper describes a carbon-13-NMR-based neural-network program, from a training set of 200 natural products, that seems to do a good job of flagging inconsistencies. It won't tell you that the assigned structure is right (there's probably a list of plausible fits for any given NMR), but it will speak up when something appears to be wrong.

And that's the mode I see this being used in, actually. I suspect that some groups will be motivated to go after the misassigned compounds synthetically, if they can come up with a believable alternative, in order to revise the structure. I'm not sure what happens if you put one of those South Pacific marine toxins into it, the ones that practically need a centerfold to publish their structures in a journal, but this looks like it could be a useful tool.

Comments (4) + TrackBacks (0) | Category: Analytical Chemistry | Natural Products

One Conspiracy After Another

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Posted by Derek

Here's a cartoon by someone who's been down the "Who are these people on the internet who think they know chemistry?" path. Many of you will be able to relate!

Comments (5) + TrackBacks (0) | Category: Snake Oil

June 24, 2013

How Robust Is That New Reaction, Anyway?

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Posted by Derek

Here's a paper in Nature Chemistry that addresses something that isn't explicitly targeted as often as it should be: the robustness of new reactions. The authors, I think, are right on target with this:

We believe a major hurdle to the application of a new chemical methodology to real synthetic problems is a lack of information regarding its application beyond the idealized conditions of the seminal report. Two major considerations in this respect are the functional group tolerance of a reaction and the stability of specific chemical motifs under reaction conditions. . .

Taking into account the limitations of the current methods, we propose that a lack of understanding regarding the application of a given reaction to non-idealized synthetic problems can result in a reluctance to apply new methodology. Confidence in the utility of a new reaction develops over time—often over a number of years—as the reaction is gradually applied within total syntheses, follow-up methodological papers are published, or personal experience is developed. Unfortunately, even when this information has evolved, it is often widely dispersed, fragmented and difficult to locate. To address this problem, both the tolerance of a reaction to chemical functionality and of the chemical functionality to the reaction conditions must be established when appropriate, and reported in an easily accessible manner, preferably alongside the new methodology.

This is as opposed to the current standard of one or two short tables of different substrates, and then a quick application to some natural product framework. Even those papers, I have to say, are better than some of the stuff in the literature, but we still could be doing better. This paper proposes an additional test: running the reaction in the presence of various added compounds, and reporting the % product that forms under these conditions, the % starting material remaining, and the % additive remaining as well. (The authors suggest using a simple, robust method like GC to get these numbers, which is good advice). This technique will give an idea of the tolerance of the reagents and catalysts to other functional groups, without incorporating them into new substrates, and can tell you if the reaction is just slowed down, or if something about the additive stops everything dead.

Applying this setup to a classic Buchwald amination reaction shows that free aliphatic and aromatic alcohols and amines kill the reaction. Esters and ketones are moderately tolerated. Extraneous heterocycles can slow things down, but not in all cases. But alkynes, nitriles, and amides come through fine: the product forms, and the additives aren't degraded.

I like this idea, and I hope it catches on. But I think that the only way it will is if editors and reviewers start asking for it. Otherwise, it'll be put in the "More work" category, which is easy for authors to ignore. If something like this became the standard, though, all of us synthetic chemists would be better off.

Comments (18) + TrackBacks (0) | Category: Chemical News | The Scientific Literature

Eight Toxic Foods: The Aftermath

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Posted by Derek

traffic%20chart.pngWell, as you can see from the graphic, my blast against the "Eight Toxic Foods" stuff picked up a lot of attention over the weekend, which I'm glad to see. A lot of this came from it being handed around Facebook, but Fark, Reddit, Popular Science's website and others all brought in plenty of traffic as well.

I've had a lot of requests for more articles like that one, but they'll be an occasional feature around here. There's certainly enough material to fill a blog that whacks away at things like the original BuzzFeed piece, and there are quite a few bloggers who've made that their turf. I don't really want to make it my daily diet, though - for one thing, there is just so much craziness out there that you start to wonder - rather quickly - if you'll ever see the end of it. I'm not sure if I can stand reading it day after day, either, just as I'm not sure that I could go on day after day writing about things that drive me crazy. But I definitely plan to keep on taking shots every so often at prominent stuff that mangles chemistry and/or drug research as part of its argument. In this latest case, it was the roaring success of the BuzzFeed piece coupled with its chirpy, confident, and bizarrely wrong takes on chemistry and toxicology that set me off.

I spent the weekend, by the way, being called a paid shill for Monsanto, DuPont, and all the other evil monied interests. It made a refreshing change from being called a paid shill for Big Pharma. Going straight to that accusation, by the way (or using it as if that's all that needs to be done) does not say a lot for the people who advance it. There's not much persuasive force behind "I don't like this, therefore the only reason anyone could be advocating it is that they've been paid to do so". What's also interesting is how some of these people act as if this is some newly discovered counterattack, that no one in the history of argument has ever thought of accusing an opponent of bad faith. What else has someone like this not come across, or not bothered to notice?

There's also a strain of Manicheanism running through a lot of the more worked-up responses: Good vs. Evil, 100% one way or or 100% the other. If I don't think that potassium bromate in flour is that big a deal, then I must think that chemical waste drums should be poured into lakes. If I don't think that 2 ppb arsenic in chicken is killing us, then I must want to feed spoonfuls of the pure stuff to infants. And so on.

Not so. As it turns out, the flour we use at home for baking (King Arthur) is not bromated, although I didn't pick it for that reason. Not being a professional baker, I doubt if I could notice a difference one way or another due to the bromate. And while (true to my Arkansas roots) I do drink a Mountain Dew every so often, I really do think that drinking gallons of the stuff day after day would be a very bad idea. The brominated vegetable oil would not be the first of your worries, but (as the medical literature shows) it could indeed catch up with some people.

There is such a thing as overloading the body's clearance mechanisms (as any medicinal chemist is well aware), and that level is different with every substance. Some things get blasted out of the body so quickly by the liver and the kidneys that you never even notice them, even at rather high doses. Others (acetaminophen is the classic example) are cleared out well under normal conditions, but can be real trouble if the usual mechanism is impaired by something else. And others (such as some radioactive isotopes, say) are actively accumulated in the body as well as being cleared from it, and therefore can have extremely low tolerance levels indeed. Every case is different; every case needs its own data and its own decision.

I am planning a follow-up post, though, based on one of the reasonable counterarguments that's come up: why are some of these ingredients banned in other countries? What reasons are behind those regulatory decisions, and why did the FDA come to different conclusions? That's worth going into details about, and I will.

Comments (65) + TrackBacks (0) | Category: Snake Oil | Toxicology

June 21, 2013

Eight Toxic Foods: A Little Chemical Education

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Posted by Derek

Update: You'll notice in this post that I refer to some sites that the original BuzzFeed article I'm complaining out sends people to, often pointing out that these didn't actually support the wilder claims it's making. Well, the folks at BuzzFeed have dealt with this by taking down the links (!) The article now says: "Some studies linked in the original version of this article were concerning unrelated issues. They have been replaced with information directly from the book Rich Food, Poor Food". But as you'll see below, the studies weren't unrelated at all. So when you read about links to the American Cancer Association or NPR, well, all I can say is that they used to be there, until someone apparently realized how embarrassing they were.

Many people who read this blog are chemists. Those who aren't often come from other branch of the sciences, and if they don't, it's safe to say that they're at least interested in science (or they probably don't hang around very long!) It's difficult, if you live and work in this sort of environment, to keep in mind what people are willing to believe about chemistry.

But that's what we have the internet for. Many science-oriented bloggers have taken on what's been called "chemophobia", and they've done some great work tearing into some some really uninformed stuff out there. But nonsense does not obey any conservation law. It keeps on coming. It's always been in long supply, and it looks like it always will be.

That doesn't mean that we just have to sit back and let it wash over us, though. I've been sent this link in the last few days, a popular item on BuzzFeed with the BuzzFeedy headline of "Eight Foods That We Eat in The US That Are Banned in Other Countries". When I saw that title, I found it unpromising. In a world that eats everything that can't get away fast enough, what possible foods could we have all to ourselves here in the States? A quick glance was enough: we're not talking about foods here - we're talking about (brace yourselves) chemicals.

This piece really is an education. Not about food, or about chemistry - on the contrary, reading it for those purposes will make you noticeably less intelligent than you were before, and consider that a fair warning. The educational part is in the "What a fool believes" category. Make no mistake: on the evidence of this article, its author is indeed a fool, and has apparently never yet met a claim about chemicals or nutrition that was too idiotic to swallow. If BuzzFeed's statistics are to be believed (good question, there), a million views have already accumulated to this crap. Someone who knows some chemistry needs to make a start at pointing out the serial stupidities in it, and this time, I'm going to answer the call. So here goes, in order.

Number One: Artificial Dyes. Here's what the article has to say about 'em:

Artificial dyes are made from chemicals derived from PETROLEUM, which is also used to make gasoline, diesel fuel, asphalt, and TAR! Artificial dyes have been linked to brain cancer, nerve-cell deterioration, and hyperactivity, just to name a few.

Emphasis is in the original, of course. How could it not lapse into all-caps? In the pre-internet days, this sort of thing was written in green ink all around the margins of crumpled shutoff notices from the power company, but these days we have to make do with HTML. Let's take this one a sentence at a time.

It is true, in fact, that many artificial dyes are made from chemicals derived from petroleum. That, folks, is because everything (edible or not) is made out of chemicals, and an awful lot of man-made chemicals are derived from petroleum. It's one of the major chemical feedstocks of the world. So why stop at artificial dyes? The ink on the flyer from the natural-foods co-op is made from chemicals derived from petroleum. The wax coating the paper wrapped around that really good croissant at that little bakery you know about is derived from petroleum.

Now, it's true that more things you don't eat can be traced back to petroleum feedstocks than can things you do eat. That's because it's almost always cheaper to grow stuff than to synthesize it. Synthesized compounds, when they're used in food, are often things that are effective in small amounts, because they're so expensive. And so it is with artificial dyes - well, outside of red velvet cake, I guess. People see the bright colors in cake icing and sugary cereals and figure that the stuff must be glopped on like paint, but paint doesn't have very much dye or pigment in it, either (watch them mix it up down at the hardware store sometime).

And as for artificial colors causing "brain cancer, nerve-cell deterioration, and hyperactivity", well, these assertions range from "unproven" all the way down to "bullshit". Hyperactivity sensitivities to food dyes are an active area of research, but after decades of work, the situation is still unclear. And brain cancer? This seems to go back to studies in the 1980s with Blue #2, where rats were fed the dye over a long period in much larger concentrations (up to 2% of their total food intake) than even the most dedicated junk-food eater could encounter. Gliomas were seen in the male rats, but with no dose-response, and at levels consistent with historical controls in the particular rat strain. No one has ever been able to find any real-world connection. Note that glioma rates increased in the 1970s and 1980s as diagnostic imaging improved, but have fallen steadily since then. The age-adjusted incidence rates of almost all forms of cancer are falling, by the way, not that you'd know that from most of the coverage on the subject.

Number Two: Olestra

This, of course, is Proctor & Gamble's attempted non-calorific fat substitute. I'm not going to spend much time on this, because little or nothing is actually made with it any more. Olestra was a major flop for P&G; the only things (as far as I can tell) that still contain it are some fat-free potato chips. It does indeed interfere with the absorption of fat-soluble vitamins, but potato chips are not a very good source of vitamins to start with. And vitamin absorption can be messed with by all kinds of things, including other vitamins (folic acid supplements can interfere with B12 absorption, just to pick one). But I can agree with the plan of not eating the stuff: I think that if you're going to eat potato chips, eat a reasonable amount of the real ones.

Number Three: Brominated Vegetable Oil. Here's the article's take on it:

Bromine is a chemical used to stop CARPETS FROM CATCHING ON FIRE, so you can see why drinking it may not be the best idea. BVO is linked to major organ system damage, birth defects, growth problems, schizophrenia, and hearing loss.

Again with the caps. Now, if the author had known any chemistry, this would have looked a lot more impressive. Bromine isn't just used to keep carpets from catching on fire - bromine is a hideously toxic substance that will scar you with permanent chemical burns and whose vapors will destroy your lungs. Drinking bromine is not just a bad idea; drinking bromine is guaranteed agonizing death. There, see what a little knowledge will do for you?

But you know something? You can say the same thing for chlorine. After all, it's right next to bromine in the same column of the periodic table. And its use in World War I as a battlefield gas should be testimony enough. (They tried bromine, too, never fear). But chlorine is also the major part, by weight, of table salt. So which is it? Toxic death gas or universal table seasoning?

Knowledge again. It's both. Elemental chlorine (and elemental bromine) are very different things than their ions (chloride and bromide), and both of those are very different things again when either one is bonded to a carbon atom. That's chemistry for you in a nutshell, knowing these differences and understanding why they happen and how to use them.

Now that we've detoured around that mess, on to brominated vegetable oil. It's found in citrus-flavored sodas and sports drinks, at about 8 parts per million. The BuzzFeed article claims that it's linked to "major organ system damage, birth defects, growth problems, schizophrenia, and hearing loss", and sends readers to this WebMD article. But if you go there, you'll find that the only medical problems known from BVO come from two cases of people who had been consuming, over a long period, 4 to 8 liters of BVO-containing soda per day, and did indeed have reactions to all the excess bromine-containing compounds in their system. At 8 ppm, it's not easy to get to that point, but a determined lunatic will overcome such obstacles. Overall, drinking several liters of Mountain Dew per day is probably a bad idea, and not just because of the BVO content.

Number Four: Potassium Bromate. The article helpfully tells us this is "Derived from the same harmful chemical as brominated vegetable oil". But here we are again: bromate is different from bromide is different than bromine, and so on. If we're going to play the "made from the same atoms" game, well, strychnine and heroin are derived from the same harmful chemicals as the essential amino acids and B vitamins. Those harmful chemicals, in case you're wondering, are carbon, hydrogen, oxygen, and nitrogen. And to get into the BuzzFeed spirit of the thing, maybe I should mention that carbon is found in every single poisonous plant on earth, hydrogen is the harmful chemical that blew up the Hindenburg, oxygen is responsible for every death by fire around the world, and nitrogen will asphyxiate you if you try to breathe it (and is a key component of all military explosives). There, that wasn't hard - as Samuel Johnson said, a man might write such stuff forever, if only he would give over his mind to it.

Now, back to potassium bromate. The article says, "Only problem is, it’s linked to kidney damage, cancer, and nervous system damage". And you'll probably fall over when I say this, but that statement is largely correct. Sort of. But let's look at "linked to", because that's an important phrase here.

Potassium bromate was found (in a two-year rat study) to have a variety of bad effects. This occurred at the two highest doses, and the lowest observed adverse effect level (LOAEL) was 6.1 mg of bromate per kilo body weight per day. It's worth noting that a study in male mice took them up to nearly ten times that amount, though, with little or no effect, which gives you some idea of how hard it is to be a toxicologist. Whether humans are more like mice or more like rats in this situation is unknown.

I'm not going to do the whole allometric scaling thing here, because no matter how you do it, the numbers come out crazy. Bromate is used in some (but not all) bread flour at 15 to 30 parts per million, and if the bread is actually baked properly, there's none left in the finished product. But for illustration, let's have someone eating uncooked bread dough at the highest level, just to get the full bromate experience. A 75-kilo human (and many of us are more than that) would have to take in 457 mg of bromate per day to get to the first adverse level seen in rats, which would be. . .15 kilos (about 33 pounds) of bread dough per day, a level I can safely say is unlikely to be reached. Hell, eating 33 pounds of anything isn't going to work out, much as my fourteen-year-old son tries to prove me wrong. You'd need to keep that up for decades, too, since that two year study represents a significant amount of a rat's lifespan.

Number Five: Azodicarbonamide. This is another bread flour additive. According to the article, "Used to bleach both flour and FOAMED PLASTIC (yoga mats and the soles of sneakers), azodicarbonamide has been known to induce asthma".

Let's clear this one up quickly: azodicarbonamide is indeed used in bread dough, and allowed up the 45 parts per million. It is not stable to heat, though, and it falls apart quickly to another compound, biurea, on baking. It not used to "bleach foamed plastic", though. Actually, in higher concentrations, it's used to foam foamed plastics. I realize that this doesn't sound much better, but the conditions inside hot plastic, you will be glad to hear, are quite different from those inside warm bread dough. In that environment, azodicarbonamide doesn't react to make birurea - it turns into several gaseous products, which are what blow up the bubbles of the foam. This is not its purpose in bread dough - that's carbon dioxide from the yeast (or baking powder) that's doing the inflating there, and 45 parts per million would not inflate much of anything.

How about the asthma, though? If you look at the toxicology of azodicarbonamide, you find that "Azodicarbonamide is of low acute toxicity, but repeated or prolonged contact may cause asthma and skin sensitization." That, one should note, is for the pure chemical, not 45 parts per million in uncooked flour (much less zero parts per million in the final product). If you're handling drums of the stuff at the plastics plant, you should be wearing protective gear. If you're eating a roll, no.

Number Six: BHA and BHT. We're on the home stretch now, and this one is a two-fer. BHA and BHT are butylated hydroxyanisole and butylate hydroxytoluene, and according to the article, they are "known to cause cancer in rats. And we’re next!"

Well, of course we are! Whatever you say! But the cancer is taking its time. These compounds have been added to cereals, etc., for decades now, while the incidence rates of cancer have been going down. And what BuzzFeed doesn't mention is that while some studies have shown an increase in cancer in rodent models with these compounds, others have shown a measurable decrease. Both of these compounds are efficient free radical scavengers, and have actually been used in animal studies that attempt to unravel the effects of free radicals on aging and metabolism. Animal studies notwithstanding, attempts to correlate human exposure to these compounds with any types of cancer have always come up negative. Contrary to what the BuzzFeed article says, by the way, BHT is indeed approved by the EU.

Weirdly, you can buy BHT in some health food stores, where anti-aging and anti-viral claims are made for it. How does a health food store sell butylated hydroxytoluene with a straight face? Well, it's also known to be produced by plankton, so you can always refer to it as a natural product, if that makes you feel better. That doesn't do much for me - as an organic chemist, I know that the compounds found in plankton range from essential components of the human diet all the way down to some of the most toxic molecules found in nature.

Number Seven: Synthetic Growth Hormones. These are the ones given to cattle, not the ones athletes give to themselves. The article says that they can "give humans breast, colon, and prostate cancer", which, given what's actually known about these substances, is a wildly irresponsible claim.

The article sends you to a perfectly reasonable site at the American Cancer Society, which is the sort of link that might make a BuzzFeed reader think that it must then be about, well, what kinds of cancer these things give you. But have a look. What you find is (first off) this is not an issue for eating beef. Bovine growth hormone (BGH) is given to dairy cattle to increase milk production. OK, so what about drinking milk?

Here you go: for one, BGH levels in the milk of treated cows are not higher than in untreated ones. Secondly, BGH is not active as a growth hormone in humans - it's selective for the cow receptor, not the human one. The controversy in this area comes from the way that growth hormone treatment in cows tends to increase levels of another hormone, IGF-1, in the milk. That increase still seems to be within the natural range of variability for IGF-1 in regular cows, but there is a slight change.

The links between IGF-1 and cancer have indeed been the subject of a lot of work. Higher levels of circulating IGF-1 in the bloodstream have (in some studies) been linked to increased risk of cancer, but I should add that other studies have failed to find this effect, so it's still unclear what's going on. I can also add, from my own experiences in drug discovery, that all of the multiple attempts to treat cancer by blocking IGF-1 signaling have been complete failures, and that might also cause one to question the overall linkage a bit.

But does drinking milk from BGH-treated cows increase the levels of circulating IGF-1 at all? No head-to-head study has been run, but adults who drink milk in general seem to have slightly higher levels. The same effect, though, was seen in people who drink soymilk, which (needless to say) does not have recombinant cow hormones in it. No one knows to what extent ingested IGF-1 might be absorbed into the bloodstream - you'd expect it to be digested like any other protein, but exceptions are known.

But look at the numbers. According to that ACA web summary, even if the protein were not degraded at all, and if it were completely absorbed (both of which are extremely unrealistic top-of-the-range assumptions), and even if the person drinking it were an infant, and taking in 1.6 quarts a day of BGH-derived cow milk with the maximum elevated levels of IGF-1 that have been seen, the milk would still contribute less than 1% of the IGF-1 in the bloodstream compared to what's being made in the human body naturally.

Number Eight, Arsenic. Arsenic? It seems like an unlikely food additive, but the article says "Used as chicken feed to make meat appear pinker and fresher, arsenic is POISON, which will kill you if you ingest enough."

Ay. I think that first off, we should make clear that arsenic is not "used as chicken feed". That brings to mind someone pitching powdered arsenic out for the hens, and that's not part of any long-term chicken-farming plan. If you go to the very NPR link that the BuzzFeed article offers, you find that a compound called roxarsone is added to chicken feed to keep down Coccidia parasites in the gut. It is not just added for some cosmetic reason, as the silly wording above would have you believe.

In 2011, a study found that chicken meat with detectable levels of roxarsone had 2.3 parts per billion (note the "b") of inorganic arsenic, which is the kind that is truly toxic. Chicken meat with no detectable roxarsone had 0.8 ppb inorganic arsenic, threefold less, and the correlation seems to be real. (Half of the factory-raised chickens sampled had detectable roxarsone, by the way). This led to the compound being (voluntarily) withdrawn from the market, under the assumption that this is an avoidable exposure to arsenic that could be eliminated.

And so it is. There are other (non-arsenic) compounds that can be given to keep parasite infestations down in poultry, although they're not as effective, and they'll probably show up on the next edition of lists like this one. But let's get things on scale: it's worth comparing these arsenic levels to those found in other foods. White rice, for example comes in at about 100 parts per billion of inorganic arsenic (and brown rice at 170 ppb). These, by the way, are all-natural arsenic levels, produced by the plant's own uptake from the soil. But even those amounts are not expected to pose a human health risk (says both the FDA and Canadian authorities), so the fifty-fold lower concentrations in chicken would, one thinks, be even less to worry about. If you're having chicken and rice and you want to worry about arsenic, worry about the rice.

This brings me to the grand wrap-up, and some of the language in that last item is a good starting point for it. I'm talking about the "POISON, which will kill you if you ingest enough" part. This whole article is soaking in several assumptions about food, about chemistry, and about toxicology, and that's one of the big ones. In my experience, people who write things like this have divided the world into two categories: wholesome, natural, healthy stuff and toxic chemical poisons. But this is grievously simple-minded. As I've emphasized in passing above, there are plenty of natural substances, made by healthy creatures in beautiful, unpolluted environments, that will nonetheless kill you in agony. Plants, fungi, bacteria, and animals produce poisons, wide varieties of intricate poisons, and they're not doing it for fun.

And on the other side of the imaginary fence, there are plenty of man-made substances that really won't do much of anything to people at all. You cannot assume anything about the effects of a chemical compound based on whether it came from a lovely rainforest orchid or out of a crusty Erlenmeyer flask. The world is not set up that way. Here's a corollary to this: if I isolate a beneficial chemical compound from some natural source (vitamin C from oranges, for example, although sauerkraut would be a good source, too), that molecule is identical to a copy of it I make in my lab. There is no essence, no vital spirit. A compound is what it is, no matter where it came from.

Another assumption that seems common to this mindset is that when something is poisonous at some concentration, it is therefore poisonous at all concentrations. It has some poisonous character to it that cannot be expunged nor diluted. This, though, is more often false than true. Paracelsus was right: the dose makes the poison. You can illustrate that in both directions: a beneficial substance, taken to excess, can kill you. A poisonous one, taken in very small amounts, can be harmless. And you have cases like selenium, which is simultaneously an essential trace element in the human diet and an inarguable poison. It depends on the dose.

Finally, I want to return to something I was saying way back at the beginning of this piece. The author of the BuzzFeed article knows painfully little about chemistry and biology. But that apparently wasn't a barrier: righteous conviction (and the worldview mentioned in the above three paragraphs) are enough, right? Wrong. Ten minutes of unbiased reading would have served to poke holes all through most of the article's main points. I've spent more than ten minutes (as you can probably tell), and there's hardly one stone left standing on another. As a scientist, I find sloppiness at this level not only stupid, not only time-wasting, but downright offensive. Couldn't anyone be bothered to look anything up? There are facts in this world, you know. Learn a few.

Comments (383) + TrackBacks (0) | Category: Current Events | Snake Oil | Toxicology

June 20, 2013

The Perfect Papers For Each Journal

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Posted by Derek

For the Journal of the American Chemical Society:
"Nanoscale Stuff That We Can Imagine Could Have Gone to Science or Nature, But It Went There First So It Ends Up Here"

"Another Row of Glowing Sample Vials"

For Chemical Communications:
"Wild, Out-There Amalgam of Three or Four Trendy Topics All at Once, All in Two Manuscript Pages, From a Chinese Lab You've Never Heard of"

"A Completely New Assay Technique That Looks Like It Should Need A Twelve-Page Paper, Here In Two Because We're First and Don't Forget It"

For Angewandte Chemie:
"An Actually Useful and Interesting Paper (We Reviewed This One, We Promise), Brought to You With a Wincing, Toe-Curling Pun in the Abstract"

"The First Plutonium-Plutonium Quintuple Bond. Who's Going to Say It Isn't?"

For the Journal of Organic Chemistry:
"Remember Us? Here's an Actual Full Paper About Some Reaction, With Experimental Details and Everything. Where Else Can You Find That, Eh?"

"A Total Synthesis That Would Have Been in JACS Back When, You Whippersnappers"

For Tetrahedron Letters
"Remember Us? Here's a Four-Page Paper About Some Reaction With No Experimental Whatsoever. Where Else Can You Find. . .Oh, Right. Never Mind."

"The Four Thousand And Forty-Seventh Way to Prepare Nitriles From Oximes"

For Organic Letters:
"A Four-Page Paper With No Experimental (Supplementary Info If You're Lucky), But One You Actually Might Want to Read"

"A New Metal-Catalyzed Coupling, Featuring a Catalyst You Can't Buy and Don't Want to Make"

For the Journal of Medicinal Chemistry:
"Big Pharma Here, With a Gigantic Flaming Viking Funeral for a Project That Chewed Up Eight Years, And Here's All We Have to Show For It?"

"Small Academic Lab Here, With A Series of Rhodanines and Polyphenols That Are Seriously Hot Leads for At Least Ten Diseases"

For Science:
"Don't See Much Synthetic Chemistry Over Here, Do You? That's How You Know This is Hot Stuff!"

"People Only Read One or Two Papers Out of Any Issue of This Journal, and This Isn't One of Them, is It?"

For Synthesis:
"As Long as There are Five-Membered Heterocyclic Systems, and German Labs to Make Every Possible Derivative of Them, We Will Survive"

For SynLett
"The Number of Four-Page Organic Chemistry Manuscripts Is Larger Than You Can Comprehend. Obviously."

For ACS Chemical Biology, ChemBioChem, Nature Chemical Biology, Chemistry and Biology, et very much al.:
"Look, We Have NMR Spectra and Cell Culture Conditions in the Same Article, and It Isn't Med-Chem, So Where Else Do We Publish? Right."

Update: I've left out some journals haven't I?

For Bioorganic and Medicinal Chemistry Letters:
"We Wanted to Publish This in J. Med. Chem., But It's Been So Long That We Lost Half the Analytical Data, So Here You Are"

"A Quick Resume-Building Paper, Part XVI, But Man, You Sure Need a Lot From This Journal to Build a Resume These Days"

For Bioorganic and Medicinal Chemistry:
"No One in History Has Ever Read This Journal Without Being Sent Here by a Literature Search, So It Doesn't Matter What Title We Give This. Cauliflower Bicycle Zip-Zang."

For Chemistry: A European Journal:
"German Flexibility, Italian Thoroughness, and the French Work Ethic Have Combined to Bring You This Research, Funded by a List of Euro-Acronyms That Takes Up Half a Page"

Comments (78) + TrackBacks (0) | Category: The Scientific Literature

June 19, 2013

The Drug Industry and the Obama Administration

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Posted by Derek

Over at Forbes, John Osborne adds some details to what has been apparent for some time now: the drug industry seems to have no particular friends inside the Obama administration:

Earlier this year I listened as a recently departed Obama administration official held forth on the industry and its rather desultory reputation. . .the substance of the remarks, and the apparent candor with which they were delivered, remain fresh in my mind, not least because of the important policy implications that the comments reflect.

. . .In part, there’s a lingering misimpression as to how new medicines are developed. While the NIH and its university research grantees make extraordinary discoveries, it is left to for-profit pharmaceutical and biotechnology companies to conduct the necessary large scale clinical studies and obtain regulatory approval prior to commercialization. Compare the respective annual spending totals: the NIH budget is around $30 billion, and the industry spends nearly double that amount. While the administration has great affection for universities, non-profit patient groups and government researchers (and it was admirably critical of the sequester’s meat cleaver impact on government sponsored research programs), it does not credit the essential role of industry in bringing discoveries from the bench to the bedside.

Terrific. I have to keep reminding myself how puzzled I was when I first came across the "NIH and universities discover all the drugs" mindset, but repeated exposures to it over the last few years have bred antibodies. If anyone from the administration would like to hear what someone who is not a lobbyist, not a CEO, not running for office, and has actually done this sort of work has to say about the topic, well, there are plenty of posts on this blog to refer to (and the comments sections to them are quite lively, too). In fact, I think I'll go ahead and link to a whole lineup of them - that way, when the topic comes up again, and it will, I can just send everyone here:

August 2012: A Quick Tour Through Drug Development Reality
May 2011: Maybe It Really Is That Hard?
March 2011: The NIH Goes For the Gusto
Feb 2011: The NIH's New Drug Discovery Center: Heading Into the Swamp?
Nov 2010: Where Drugs Come From: The Numbers
August 2009: Just Give It to NIH
August 2009: Wasted Money, Wasted Time?
July 2009: Where Drugs Come From, and How. Once More, With A Roll of the Eyes
May 2009: The NIH Takes the Plunge
Sep 2007: Drugs From Where?
November 2005: University of Drug Discovery?
October 2005: The Great Divide
September 2004: The NIH in the Clinic
September 2004: One More On Basic Research and the Clinic
September 2004: A Real-World Can O' Worms
September 2004: How Much Basic Research?
September 2004: How It Really Works

There we go - hours of reading, and all in the service of adding some reality to what is often a discussion full of unicorn burgers. Back to Osborne's piece, though - he goes on to make the point that one of the other sources of trouble with the administration is that the drug industry has continued to be profitable during the economic downturn, which apparently has engendered some suspicion.

And now for some 100-proof politics. The last of Osborne's contentions is that the administration (and many legislators as well) see the Medicare Part D prescription drug benefit as a huge windfall for the industry, and one that should be rolled back via a rebate program, setting prices back to what gets paid out under the Medicaid program instead. Ah, but opinions differ on this:

It’s useful to recall that former Louisiana Congressman and then PhRMA head Billy Tauzin negotiated with the White House in 2009 on behalf of the industry over this very question. Under the resulting deal, the industry agreed to support passage of the ACA and to make certain payments in the form of rebates and fees that amounted to approximately $80 billion over ten years; in exchange the administration agreed to resist those in Congress who pressed for more concessions from the drug companies or wanted to impose government price setting. . .

Tauzin's role, and the deal that he helped cut, have not been without controversy. I've always been worried about deals like this being subject to re-negotiations whenever it seems convenient, and those worries are not irrational, either:

. . .The White House believes that the industry would willingly (graciously? enthusiastically?) accept a new Part D outpatient drug rebate. Wow. The former official noted that the Simpson-Bowles deficit reduction panel recommended it, and its report was favorably endorsed by no less than House Speaker Boehner. Apparently, it is inconceivable to the White House that Boehner’s endorsement of the Simpson-Bowles platform would have occurred without the industry’s approval. Wow, again. That may be a perfectly logical assumption, but the other industry representatives within earshot never imagined that they had endorsed any such thing. No, it’s clear they have been under the (naïve) impression that the aforementioned $80 billion “contribution” was a very substantial sum in support of patients and the government treasury – and offered in a spirit of cooperation in recognition of the prospective benefits to industry of the expanded coverage that lies at the heart of Obamacare. With that said, the realization that this may be just the first of several installment payments left my colleagues in stunned silence; some mouths were visibly agape.

This topic came up late last year around here as well. And it'll come up again.

Comments (37) + TrackBacks (0) | Category: Academia (vs. Industry) | Current Events | Drug Development | Regulatory Affairs

June 18, 2013

New Photos, Same Blather

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Posted by Derek

I've been meaning for some time to put up some new photos on the site, what with the original one being over ten years old by now. So here we are - a progress through time. The beard remains a constant, and I still have the T. S. Eliot paperback that I'm reading in the 1983 shot. That's an old flash column next to me, drying out because I was too lazy to clean it out, and some TLC plates on the bench. I was doing carbohydrate chemistry, forming nitrones and doing cycloadditions, and I'm not at all sure that I've ever done a nitrone reaction since!

Comments (25) + TrackBacks (0) | Category: Blog Housekeeping

Forcing Fungi to Make Stranger Compounds

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Posted by Derek

Natural products come up around here fairly often, as sources of chemical diversity and inspiration. Here's a paper that combines them with another topic (epigenetics) that's been popular around here as well, even if there's some disagreement about what the word means.

A group of Japanese researchers were looking at the natural products derived from a fungus (Chaetomium indicum). Recent work has suggested that fungi have a lot more genes/enzymes available to make such things than are commonly expressed, so in this work, the team fed the fungus an HDAC inhibitor to kick its expression profile around a bit. The paper has a few references to other examples of this technique, and it worked again here - they got a significantly larger amount of polyketide products out of the fermentation, included several that had never been described before.

There have been many attempts to rejigger the synthetic machinery in natural-product-producing organisms, ranging from changing their diet of starting materials, adding environmental stresses to their culture, all the way to manipulating their actual
genomic sequences directly. This method has the advantage of being easier than most, and the number of potential gene-expression-changing compounds is large. Histone deacetylase inhibitors alone have wide ranges of selectivity against members of the class, and then you have the reverse mechanism (histone actyltranferase), methyltransferase and demethylase inhibitors, and many more. These should be sufficient to produce weirdo compounds a-plenty.

Comments (4) + TrackBacks (0) | Category: Chemical Biology | Natural Products

Bernard Munos on The Last Twelve Years of Pharma

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Posted by Derek

Bernard Munos (ex-Lilly, now consulting) is out with a paper reviewing the approved drugs from 2000 to 2012. What's the current state of the industry? Is the upturn in drug approvals over the last two years real, or an artifact? And is it enough to keep things going?

Over that twelve-year span, the average drug approvals ran at 27 per year. Half of all the new drugs were in three therapeutic areas: cancer, infectious disease, and CNS. And as far as mechanisms go, there were about 190 different ones, by Munos' count. The most crowded category was (as might have been guessed) the 17 tyrosine kinase inhibitors, but 85% of the mechanisms were used by only one or two drugs, which is a long tail indeed.

Half those mechanisms were novel - that is, they were not represented by drugs approved before 2000. Coming up behind these first-in-class mechanisms were 29 follow-on drugs during this period, with an average gap of just under three years between the first and second drugs. What that tells you is that the follower programs were started at either about the same time as the first-in-class compounds (and had a slightly longer path through development), or were started at the first opportunity once the other program or mechanism became known. This means that they were started on very nearly the same risk basis as the original program: a three-year gap is not enough to validate much for a new mechanism, other than the fact that another organization thinks that it's worth working on, too. (Don't laugh at that one - there are research department that seem to live only for this validation, and regard their own first-in-class ideas with fear and suspicion).

Overall, though, Munos says that that fast-follower approach doesn't seem to be very effective, or not any more, given that few targets seem to be yielding more than one or two drugs. And as just mentioned, the narrow gap between first and second drugs also suggests that the risk-lowering effect of this strategy isn't very impressive, either.

Here's another interesting/worrisome point:

The long tail (of the mode-of-action curve). . . suggests that pharmaceutical innovation is a by-product of exploration, and not the result of pursuing a limited set of mechanisms, reflecting, for instance, a company’s marketing priorities. Put differently, there does not seem to be enough mechanisms able to yield multiple drugs, to support an industry. . .The last couple of years have seen an encouraging rise in new drug approvals, including many based on novel modes of action. However that surge has benefited companies unequally, with the top 12 pharmaceutical companies only garnering 25 out of 68 NMEs (37%). This is not enough to secure their future.

Looking at what many (most?) of the big companies are going through right now, it's hard to argue with that point of view. The word "secure" does not appear within any short character length of "future" when you look through the prospects for Lilly, AstraZeneca, and others.

Note also that part about how what a drug R&D operation finds isn't necessarily what it was looking for. That doesn't mesh well with some models of managment:

The drug hunter’s freedom to roam, and find innovative translational opportunities wherever they may lie is an essential part of success in drug research. This may help explain the disappointing performance of the programmatic approaches to drug R&D, that have swept much of the industry in the last 15 years. It has important managerial implications because, if innovation cannot be ordained, pharmaceutical companies need an adaptive – not directive – business model.

But if innovation cannot be ordained, why does a company need lots of people in high positions to ordain it, each with his or her own weekly meeting and online presentations database for all the PowerPoint slides? It's a head-scratcher of a problem, isn't it?

Comments (29) + TrackBacks (0) | Category: Drug Development | Drug Industry History

June 17, 2013

Pay-to-Delay: Not Necessarily Illegal, But Not Long For The World

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Posted by Derek

The Supreme Court has another ruling that affects the drug industry: FTC v. Actavis took up the question of "pay to delay", the practice of paying generic companies to go away and not challenge a branded drug. Actavis was in the process of bringing a version of Solvay's AndroGel to market, claiming that the Solvay patent was invalid. They won that case, and the FDA approved their generic version, but Solvay turned around and paid them (and Paddock, another generic firm) to not bring any such drug to the market.

The Federal Trade Commission (FTC) filed suit, alleging that re- spondents violated §5 of the Federal Trade Commission Act by unlawfully agreeing to abandon their patent challenges, to refrain from launching their low-cost generic drugs, and to share in Solvay’s monopoly profits. The District Court dismissed the complaint. The Eleventh Circuit concluded that as long as the anticompetitive effects of a settlement fall within the scope of the patent’s exclusionary potential, the settlement is immune from antitrust attack. Noting that the FTC had not alleged that the challenged agreements excluded competition to a greater extent than would the patent, if valid, it affirmed the complaint’s dismissal. It further recognized that if parties to this sort of case do not settle, a court might declare a patent invalid. But since public policy favors the settlement of disputes, it held that courts could not require parties to continue to litigate in order to avoid antitrust liability.

And now the Supreme Court reverses the Eleventh Circuit. The FTC, they hold, should have been given a chance to make its antitrust case. The Court makes a point out of declining to hold such agreements "presumptively unlawful", but gives a guide to breaking them down. There are both patent validity questions and anticompetitive questions involved, they point out, and these are separate issues (and because of that, they might not take forever to litigate, as the Eleventh Circuit decision worried about). Besides, as the justices note, a sudden large payment in such a case could be a reasonable indication of the underlying patent's validity (and chances of holding up to a determined challenge). The Hatch-Waxman Act has a generally pro-competitive bent to it, and that should operate in this situation as well.

I think this is the decision that most people expected (it's certainly the one I did). Pay-to-delay has always had an antitrust-violation smell to it. The Supreme Court has now gone on record as saying that this scent may well be no illusion, and at the very least, the FTC should be able to make a case if it can. I suspect that we're going to see fewer of these deals now - perhaps none at all - because I doubt many of them would hold up.

Comments (3) + TrackBacks (0) | Category: Patents and IP | Regulatory Affairs

GPCRs Are As Crazy As You Thought

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Posted by Derek

That's my take-away from this paper, which takes a deep look at a reconstituted beta-adrenergic receptor via fluorine NMR. There are at least four distinct states (two inactive ones, the active one, and an intermediate), and the relationships between them are different with every type of ligand that comes in. Even the ones that look similar turn out to have very different thermodynamics on their way to the active state. If you're into receptor signaling, you'll want to read this one closely - and if you're not, or not up for it, just take away the idea that the landscape is not a simple one. As you'd probably already guessed.

Note: this is a multi-institution list of authors, but it did catch my eye that David Shaw of Wall Street's D. E. Shaw does make an appearance. Good to see him keeping his hand in!

Comments (6) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | In Silico

Aggravating Aggregators

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Posted by Derek

Compound aggregation is a well-known problem in biochemical assays (although if you go back a few years, that certainly wasn't the case). Some small molecules will start to bunch up under some assay conditions, and instead of your target protein getting inhibited by a single molecule of your test compound, the protein could look as if it's been inhibited by virtue of being dragged into a huge sticky clump of Test Compound Aggregate.

A group at Boehringer Ingleheim has a paper out in J. Med. Chem. suggesting a simple NMR readout to see if a given compound is showing aggregation behavior. It looks useful, but there's one thing I would add to it. The authors mention that they used a simple sodium phosphate buffer for their experiments, and that similar trends were observed in others (for a "limited set of compounds"). But I've heard Tony Giannetti of Genentech speak on this subject before (with reference to his specialty, surface plasmon resonance assays), and he's been pretty adamant about how situation-dependent aggregation can be.

The Shoichet lab's "Aggregator Advisor" page agrees. My worry is that some people might read this new paper and be tempted to clean their screening sets out up front, but you could throw some useful compounds out that way. But aggregation, annoyingly, appears to be a case-by-case thing. Probably the best ways to guard against it are (1) see if your assay can be run with detergent in it to start with, and be prepared to vary the amount, and (2) take your screening hits of interest and check them out individually before you decide that you're on to something. This new NMR assay would be a good way to do that, using the buffer that your screen was run in.

Another note that comes up in all discussions of aggregators is that while many of them are condition-specific, others have a wider range. Many "frequent hitter" compounds turn out to aggregate under a variety of conditions. In that case (because you've got empirical data from your own assays), it's really worth going back and flagging those things. It would seem worthwhile to go through any screening collection and pitch out the individual compounds that show up time and time again, since these are surely less likely to lead to anything useful. Some of these will, on closer inspection, turn out to be promiscuous aggregators, but there are other mechanisms for nastiness as well. In extreme cases, whole structural motifs should be given the fishy eye.

Comments (6) + TrackBacks (0) | Category: Drug Assays

June 14, 2013

Making Changes Inside Merck's R&D

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Posted by Derek

I've heard from more than one source that Roger Perlmutter has been shaking things up this week at Merck. Since he only took over R&D in March, that's a pretty short lag time - if these reports are accurate, he clearly has some strong opinions and is ready to act on them. From what I've been hearing, bench-level people aren't being affected. It's all in the managerial levels. Anyone with more knowledge and a willingness to share it is welcome to do so in the comments. . .

Comments (115) + TrackBacks (0) | Category: Current Events

One. . .Million. . .Pounds (For a New Antibiotic?)

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Posted by Derek

Via Stuart Cantrill on Twitter, I see that UK Prime Minister David Cameron is prepared to announce a prize for anyone who can "identify and solve the biggest problem of our time". He's leaving that open, and his examples are apparently ". . .the next penicillin, aeroplane or world wide web".

I like the idea of prizes for research and invention. The thing is, the person who invents the next airplane or World Wide Web will probably do pretty well off it through the normal mechanisms. And it's worth thinking about the very, very different pathways these three inventions took, both in their discovery and their development. While thinking about that, keep in mind the difference between those two.

The Wright's first powered airplane, a huge step in human technology, was good for carrying one person (lying prone) for a few hundred yards in a good wind. Tim Berners-Lee's first Web page, another huge step, was a brief bit of code on one server at CERN, and mostly told people about itself. Penicillin, in its early days, was famously so rare that the urine of the earliest patients was collected and extracted in order not to waste any of the excreted drug. And even that was a long way from Fleming's keen-eyed discovery of the mold's antibacterial activity. A more vivid example than penicillin of the need for huge amounts of development from an early discovery is hard to find.

And how does one assign credit to the winner? Many (most) of these discoveries take a lot of people to realize them - certainly, by the time it's clear that they're great discoveries. Alexander Fleming (very properly) gets a lot of credit for the initial discovery of penicillin, but if the world had depended on him for its supply, it would have been very much out of luck. He had a very hard time getting anything going for nearly ten years after the initial discovery, and not for lack of trying. The phrase "Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin" properly assigns credit to a lot of scientists that most people have never heard of.

Those are all points worth thinking about, if you're thinking about Cameron's prize, or if you're David Cameron. But that's not all. Here's the real kicker: he's offering one million pounds for it ($1.56 million as of this morning). This is delusional. The number of great discoveries that can be achieved for that sort of money is, I hate to say, rather small these days. A theoretical result in math or physics might certainly be accomplished in that range, but reducing it to practice is something else entirely. I can speak to the "next penicillin" part of the example, and I can say (without fear of contradiction from anyone who knows the tiniest bit about the subject) that a million pounds could not, under any circumstances, tell you if you had the next penicillin. That's off by a factor of a hundred, if you just want to take something as far as a solid start.

There's another problem with this amount: in general, anything that's worth that much is actually worth a lot more; there's no such thing as a great, world-altering discovery that's worth only a million pounds. I fear that this will be an ornament around the neck of whoever wins it, and little more. If Cameron's committee wants to really offer a prize in line with the worth of such a discovery, they should crank things up to a few hundred million pounds - at least - and see what happens. As it stands, the current idea is like me offering a twenty-dollar bill to anyone who brings me a bar of gold.

Comments (28) + TrackBacks (0) | Category: Current Events | Drug Industry History | Infectious Diseases | Who Discovers and Why

A Beta-Secretase Inhibitor Hits the Skids in Alzheimer's

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Posted by Derek

The brutal drumbeat of Alzheimer's clinical failure continues at Eli Lilly. After the Phase III failure of their gamma-secretase inhibitor semagacestat, and a delusional attempt to pretend that the anti-amyloid antibody solanezumab succeeded, now comes word that the company has halted studies of a beta-secretase inhibitor.

This one wasn't for efficacy, but for tox. The company says that LY2886721 led to abnormalities in liver function, which is the sort of thing that can happen to anyone in Phase II. There is that thioamidine thing in it, but overall, it's not a bad-looking compound, particularly by the standards of beta-secretase inhibitors. But what does that avail one? We'll never find out what this one would have done in a real Phase III trial, although (unfortunately) I know how I'd lay the odds, considering what we know about Alzheimer's drug in the clinic. Beta-secretase inhibitors are an even higher-stakes bet than usual in this field, because mechanistically they have pretty strong support when it comes to inhibiting the buildup of amyloid protein, but they also have clear mechanistic liabilities: the enzyme seems to be important in the formation of myelin sheaths, which is not the sort of thing you'd want to touch in a patient population that's already neurologically impaired. Which effect wins out in humans? Does a BACE inhibitor really lower amyloid in the clinic? And does lowering amyloid in this way really affect the progression of Alzheimer's disease? Extremely good questions, all of those, and the only way to answer them is to round up a plausible drug candidate (not so easy for this target), half a billion dollars (for starters) and try it out.

This failure makes Lilly perhaps the first company to achieve a dread milestone, the Amyloid Trifecta. They have now wiped out on beta-secretase, on gamma-secretase, and on antibody therapy. And you know, I have to salute them for it. They've been making a determined effort against a terrible disease, trying all the most well-founded means of attack, and they're getting hammered into the ground like a tent peg for it. Alzheimer's. At the rate things are going, Lilly is going to end up in a terrible position, and a lot of it has to do with battering themselves against Alzheimer's. Remember this next time someone tells you about how drug companies are just interested in ripping off each other's baldness cures or something.

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

June 13, 2013

The Supreme Court Rules on Myriad

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Posted by Derek

Just a little while ago, the Supreme Court issued a unanimous decision (rare these days) in the Myriad Genetics case. I summarized the state of play up until the most recent arguments here, and if you're just getting up to speed on this issue, I'd read that post first. There are a lot of things this case is not about, and there are a lot of headlines that are going to mess things up. I would not be surprised to see "Myriad Wins" and "Myriad Loses" coming up at the same time in a news search.

Here's the actual decision (PDF), and here's the key statement:

A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.

The earlier appeals court decision was broader, and found that isolated stretches of otherwise natural DNA were, in fact, patent-eligible, because they are not found as such (unwound, de-histoned, cleaved at both ends) in nature. But this ruling dials that back a bit. A cDNA, stripped of introns, etc., is indeed a work of human ingenuity, and is patent-eligible (as indeed, it had been considered to be before this decision). Here's more:

It is important to note what is not implicated by this decision. First, there are no method claims before this Court. Had Myriad created an innovative method of manipulating genes while searching for the BRCA1 and BRCA2 genes, it could possibly have sought a method pat- ent. But the processes used by Myriad to isolate DNA were well understood by geneticists at the time of Myriad’s patents “were well understood, widely used, and fairly uniform insofar as any scientist engaged in the search for a gene would likely have utilized a similar approach,” 702 F. Supp. 2d, at 202–203, and are not at issue in this case.

Similarly, this case does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes. Judge Bryson aptly noted that, “[a]s the first party with knowledge of the [BRCA1 and BRCA2] sequences, Myriad was in an excellent position to claim applications of that knowledge. Many of its unchallenged claims are limited to such applications.” 689 F. 3d, at 1349. Nor do we consider the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Scientific alteration of the genetic code presents a different inquiry, and we express no opinion about the application of §101 to such endeavors. We merely hold that genes and the information they encode are not patent eligible under §101 simply because they have been isolated from the surrounding genetic material.

Unfortunately, many of the news blurbs on this issue are smudging these questions around. I don't actually expect this ruling to have much effect, to be honest, except as a way to help resolve the question of whether stretches of raw DNA are patentable. The glory days of trying to patent such things are long gone, in any case. And since there are many more useful forms which are patentable, any headlines about "No patents for DNA!" are misleading.

Comments (37) + TrackBacks (0) | Category: Patents and IP

Watching DNA Polymerase Do Its Thing

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Posted by Derek

Single-molecule techniques are really the way to go if you're trying to understand many types of biomolecules. But they're really difficult to realize in practice (a complaint that should be kept in context, given that many of these experiments would have sounded like science fiction not all that long ago). Here's an example of just that sort of thing: watching DNA polymerase actually, well, polymerizing DNA, one base at a time.

The authors, a mixed chemistry/physics team at UC Irvine, managed to attach the business end (the Klenow fragment) of DNA Polymerase I to a carbon nanotube (a mutated Cys residue and a maleimide on the nanotube did the trick). This give you the chance to use the carbon nanotube as a field effect transistor, with changes in the conformation of the attached protein changing the observed current. It's stuff like this, I should add, that brings home to me the fact that it really is 2013, the relative scarcity of flying cars notwithstanding.

The authors had previously used this method to study attached lysozyme molecules (PDF, free author reprint access). That second link is a good example of the sort of careful brush-clearing work that has to be done with a new system like this: how much does altering that single amino acid change the structure and function of the enzyme you're studying? How do you pick which one to mutate? Does being up against the side of a carbon nanotube change things, and how much? It's potentially a real advantage that this technique doesn't require a big fluorescent label stuck to anything, but you have to make sure that attaching your test molecule to a carbon nanotube isn't even worse.
KF%20graphic.jpg
It turns out, reasonably enough, that picking the site of attachment is very important. You want something that'll respond conformationally to the actions of the enzyme, moving charged residues around close to the nanotube, but (at the same time) it can't be so crucial and wide-ranging that the activity of the system gets killed off by having these things so close, either. In the DNA polymerase study, the enzyme was about 33% less active than wild type.

And the authors do see current variations that correlate with what should be opening and closing of the enzyme as it adds nucleotides to the growing chain. Comparing the length of the generated DNA with the FET current, it appears that the enzyme incorporates a new base at least 99.8% of the time it tries to, and the mean time for this to happen is about 0.3 milliseconds. Interestingly, A-T pair formation takes a consistently longer time than C-G does, with the rate-limiting step occurring during the open conformation of the enzyme in each case.

I look forward to more applications of this idea. There's a lot about enzymes that we don't know, and these sorts of experiments are the only way we're going to find out. At present, this technique looks to be a lot of work, but you can see it firming up before your eyes. It would be quite interesting to pick an enzyme that has several classes of inhibitor and watch what happens on this scale.

It's too bad that Arthur Kornberg, the discoverer of DNA Pol I, didn't quite live to see such an interrogation of the enzyme; he would have enjoyed it very much, I think. As an aside, that last link, with its quotes from the reviewers of the original manuscript, will cheer up anyone who's recently had what they thought was a good paper rejected by some journal. Kornberg's two papers only barely made it into JBC, but one year after a referee said "It is very doubtful that the authors are entitled to speak of the enzymatic synthesis of DNA", Kornberg was awarded the Nobel for just that.

Comments (5) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | The Scientific Literature

June 12, 2013

Product Inhibition, Or Grinding To A Halt

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Posted by Derek

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.

Comments (12) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

Influential Chemists, Anyone?

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Posted by Derek

ChemBark has an interesting question here: who's the most respected and influential chemist, among chemists? He was taking nominations on Twitter, and has settled on Roald Hoffman as his choice. Other strong contenders included Nocera, Corey, Whitesides, Sharpless, Kroto, Grubbs, Gray, Hershbach, Zare, and Stoddart. Anyone over here have names to add to the list? Note again that we're talking influence and fame inside the field, because if you go to "among the general public", you pretty much cut everyone out right there, unfortunately. . .

Comments (70) + TrackBacks (0) | Category: Chemical News

June 11, 2013

The Overselling of Ionic Liquids

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Posted by Derek

Ionic liquids (molten salts at relatively low temperatures) have been a big feature of the chemical literature for the last ten or fifteen years - enough of a feature to have attracted a few disparaging comments here, from me and from readers. There's a good article out now that talks about the early days of the field and how it grew, and it has some food for thought in it.

The initial reports in the field didn't get much attention (as is often the case). What seems to have made things take off was the possibility of replacing organic solvents with reusable, non-volatile, and (relatively) non-toxic alternatives. "Green chemistry" was (and to an extent still is) a magnet for funding, and it was the combination of this with ionic liquid (IL) work that made the field. But not all of this was helpful:

The link with green chemistry during the development of the IL field, propelled both fields forward, but at times the link was detrimental to both fields when overgeneralizations eroded confidence. ILs were originally considered as green since many of these liquid salts possess a negligible vapor pressure and might replace the use of volatile organic solvents known to result in airborne chemical contamination. The reported water stability and non-volatility led to the misconception that these salts were inherently safe and environmentally friendly. This was exacerbated by the many unsubstantiated claims that ILs were ‘green’ in introductions meant to provide the motivation for the study, even if the study itself had nothing to do with green chemistry. While it is true that the replacement of a volatile organic compound (VOC) might be preferred, proper knowledge of the chemistry of the ions must also be taken into account before classifying anything as green. Nonetheless, the statement “Ionic Liquids are green” was widely published (and can still be found in papers published today). Given the number and nature of the possible ions comprising ILs, these statements are similar to “Water is green, therefore all solvents are green.”

There were many misunderstandings at the chemical level as well:

However, just as the myriad of molecular solvents (or any compounds) can have dramatic differences in chemical, physical, and biological properties based on their chemical identity, so too can ILs. With the potential for 10^18 ion combinations, a single crystal structure of one compound is not a good representation of the chemistry of the entire class of salts which melt below 100 °C and would be analogous to considering carbon tetrachloride as a model system for all known molecular solvents.

The realization that hexafluorophosphate counterions can indeed generate HF under the right conditions helped bring a dose of reality back to the field, although (as the authors point out), not without a clueless backlash that decided, for a while, that all ionic liquids were therefore intrinsically toxic and corrosive. The impression one gets is that the field has settled down, and that its practitioners are more closely limited to people who know what they are talking about, rather than having quite so many who are doing it because it's hot and publishable. And that's a good thing.

Comments (12) + TrackBacks (0) | Category: Chemical News | The Scientific Literature

More on the GSK Shanghai Scandal

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Posted by Derek

The accusations of data fabrication at GlaxoSmithKline's China research site are quite real. That's what we get from the latest developments in the case, as reported by BioCentury, Pharmalot, and the news section at Nature Medicine. Jingwu Zang, lead author on the disputed paper and former head of the Shanghai research site, has been dismissed from the company. Other employees are on administrative leave while an investigation proceeds, and GSK has said it has begun the process of retracting the paper itself.

As for what's wrong with the paper in question, BioCentury Extra has this:

GSK said data in a paper published in January 2010 in Nature Medicine on the role of interleukin-7 (IL-7) in autoimmune disease characterized data as the results of experiments conducted with blood cells of multiple sclerosis (MS) patients "when, in fact, the data reported were either the results of experiments conducted at R&D China with normal (healthy donor) samples or cannot be documented at all, suggesting that they well may have been fabricated."

Pharmalot and others also report that GSK is asking all the authors of the paper to sign documents to agree that it be retracted, which is standard procedure at the Nature Publishing Group. If there's disagreement among them, the situation gets trickier, but we'll see what happens.

The biggest questions are unanswered, though, and we're not likely to hear about them except in rumors and leaks. How, for one thing, did this happen in the first place? On whose initiative were results faked? Who was supposed to check up on these results, and was there anything that could have been done to catch this problem earlier? Even more worrying - and you can bet that plenty of people inside GSK are thinking this, too - how many more things have been faked as well? You'd hope that this was an isolated incident, but if someone is willing to whip up a batch of lies like this, they might well be willing to do much more besides.

The involvement of the head of the entire operation (Jingwu Zang) is particularly troubling. Sometimes, in such cases, it turns out that the person at the top just had their name on the paper, but didn't really participate much or even know what was going on. But he's the only person so far in this mess who's been outright fired, which suggests that something larger has happened. We're not going to hear much about it, but you can bet there are some rather worried and upset people digging through this inside GlaxoSmithKline. There had better be.

Comments (30) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 10, 2013

Getting Your Hands on All Those Three-Dimensional Structures

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Posted by Derek

The topic of making hit compounds, leads, and drug candidates that are less flat/aromatic has come up several times around here, and constantly around the industry. A reader sent along the following question: supposing that you wanted to obtain a decent collection of molecules with a greater-than-normal number of nonaromatic carbons and chiral centers, where would you find them?

Are there some suppliers that have done a better job than others of rising to the demand for this sort of thing? If anyone has nominations for good sources, or for places that are at least showing signs of moving in that direction, they'd be welcome. My guess is that fragment-sized molecules would be a good place to start, since they're (presumably) more synthetically accessible, and have advantages in the amount of chemical space that can be covered per number of compounds, but all comers will be considered. . .

Comments (12) + TrackBacks (0) | Category: Chemical News

Deuterated Drugs: An Obvious Idea?

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Posted by Derek

Nature Medicine has an update on the deuterated drug landscape. There are several compounds in the clinic, and the time to the first marketed deuterium-containing drug is surely counting down.

But, as mentioned at the end of that piece, another countdown that also must be ticking away is the one to the first lawsuit. There are several places where one could be fought out. The deuterated-drug landscape was the subject of a vigorous early land rush, and there are surely overlapping claims out there which will have to be sorted out if (when) the money starts to flow from the idea. And there's the whole problem of obviousness, a key patent-killer. The tricky thing is, standards of what is obvious to one skilled in the art change over time. They have to change; the art changes. (I'll risk some more gritted teeth among the readership by breaking into Latin again: Tempora mutantur, nos et mutamur in illis.

We've already seen this with respect to single enantiomers - it's now considered obvious to resolve a racemic mixture, an to expect that the two isomers will have different activities as pharmaceuticals. At what point will it be considered obvious that deuteration can improve the pharmacokinetics? If that does ever happen, it'll take longer, because deuteration is not as simple a process as resolution of a racemate. Itt can be difficlut (and, well, non-obvious) to figure out where to put the deuteriums for maximum effect, and how many need to be added. Adding them is not always so easy, either, which brings up questions of enablement and reduction to practice. You need to teach toward the compounds you want to claim, and for deuteration, that's going to mean getting pretty specific.

There's another consideration that I hadn't been aware of until this weekend. I had the chance to talk with a patent attorney at a social gathering (not everyone's idea of a big Saturday night, admittedly, but I enjoyed the whole affair). He was explaining to me a consequence of the Supreme Court's recent ruling on obviousness, the 2007 KSR v. Teleflex decision. Apparently, one of the major effects of that ruling was the idea that if there are a limited number of known options for an inventor to choose from, that can take the whole thing into the realm of the obvious. The actual language is that when ". . .there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. . .the fact that a combination was obvious to try might show that it was obvious under § 103". You can see the PTO itself trying to come to grips with KSR here, and it seems to be very heavily cited indeed by examiners (and in subsequent court cases).

Naturally, as with legal matters, the big question becomes exactly what a limited number of options might mean. How many, exactly, is that? In the case of a racemate, you have two (only two, always two), and it's certainly reasonable to expect them to be different in vivo. So that would come under the KSR principle, I'd say, and it's not just me. But what if there are a limited number of places that a deuterium can be added to a molecule? At what point does deuterating them become, well, just one of those things that a person skilled in the art would know to try?

Expect a court case on this eventually, when some serious money starts to be made in the area. This is going to be fought out case by case, and it's going to take quite a while.

Comments (30) + TrackBacks (0) | Category: Patents and IP | Pharmacokinetics

June 7, 2013

Mutato Nomine De Te Fabula Narratur

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Posted by Derek

Reader may remember the sudden demise of science-fraud.org, under threats of legal action. Its author, Paul Brookes, had a steady stream of material pointing out what very much seemed to be altered and duplicated figures in many scientific publications.

Now comes word that the Brazilian researcher (Rai Curi) whose legal threats led to that shutdown has corrected yet another one of his publications. That Retraction Watch link has the details, but I wanted to highlight the corrections involved:

After the publication of this manuscript we observed mistakes in Figures 3A, 4A, and 6A. The representative images related to pAkt (Figure 3A), mTOR total (Figure 4A), and MuRF-1 total (Figure 6A) have been revised. Please note the original raw blots are now provided with the revised Figures as part of this Correction.
In Figure 3A, pAkt panel, the C and CS bands had been duplicated.
In Figure 4A, the bands were re-arranged compared to the original blot.
In Figure 6A, the band for group D was incorrect.

The remaining Figures, results and conclusions are the same as originally reported in the article. The authors apologize for these errors and refer readers to the corrected Figures 3A, 4A, and 6A provided in this Correction.

So I'm certainly glad that Prof. Curi went after a web site that looks for rearranged blots and altered gels. We wouldn't want any of that around. Would we, now.

Comments (32) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

Making Peroxides, Quietly And Unhelpfully

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Posted by Derek

Here's a problem with screening collections that I have to admit I wasn't aware of: generation of hydrogen peroxide. This paper (free access) gives an excellent overview of what's going on. Turns out that some compounds can undergo redox-cycling in the presence of the common buffer additive DTT (dithiothreitol - note - fixed brain spasm on earlier name), spitting out, in the end, a constant trickle of peroxide.

Now, for many assays, this might not mean much one way or another. But enzymes with a crucial cysteine residue are another matter. Those can get oxidized, which is irritating in these cases, because DTT is added to such assays just to keep that sort of thing from happening. That link above describes a useful horseradish peroxidase/phenol red assay to detect hydrogen peroxide generation, and its use to profile the NIH's Small Molecule Repository compound collections.

Fortunately, only a limited number of compounds have the ability to hose up your assays in this manner. Of the roughly 196,000 compounds screened, only 37 were true peroxide-generators. Quinones are serial offenders, as any chemist might expect, but if you let you screening collection fill up with quinones you have only yourself to blame. There are less obvious candidates, though: several arylsulfonamides also showed this behavior, and while those aren't everyone's favorite compounds, I'd like to see the large screening set that doesn't have some in there somewhere. It's worth noting, though, that many of the sulfonamides that were identified are also quinon-ish.

So I think the take-home advice here is to be aware if your target is sensitive to this sort of thing. Cysteine proteases are obvious candidates, but Trp can be oxidized, too, and a lot of proteins have crucial disulfides that might get unraveled. Once you've flagged your protein as a concern, be sure to run the hits you get back through this peroxide assay to make sure that you're not being led on. Trying to eliminate compounds by structural class up front is another approach, but the compounds that are first on the list are compounds that you should have trashcanned already.

Comments (7) + TrackBacks (0) | Category: Drug Assays

Five Minutes With Any Journal Article You Want?

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Posted by Derek

The literature access service DeepDyve has made an intriguing announcement of a new service they're offering for non-subscribers of scientific journals. For free, you can have access to the full text. . .for five minutes.

Here's more from the Information Culture blog at Scientific American. Obviously, five minutes is not enough to actually read a journal article, but it probably is enough to decide if you really want to pay to see the thing for real. (And I might note, for chemists and biologists, that five minutes is probably enough time to check a procedure in the experimental section). To that end, it's worth noting that many journals do not seem to put their Supplementary Information files behind their paywalls, and thorough experimental details seem more and more to be showing up in those, rather than the main text.

Note: DeepDyve has access to Elsevier, Wiley, and Royal Society of Chemistry journals, among many others. Nature is in there, but not ScienceBut appears to be no Journal of Biological Chemistry, to pick a heavy hitter on the bio end. And for the less-common chemistry needs, there appears to be no access to Heterocycles or the Journal of Heterocyclic Chemistry, and no Phosphorus, Sulfur, although many other out-of-the-way journals do show up. Update: note also that the American Chemical Society does not seem to be a participant at all. . .

But for people without journal access, this could be the best of a number of not-so-good options. I'll give it a try myself next time I run into some reference in a journal that my own institution doesn't subscribe to, and see how it goes. Thoughts and experiences welcome in the comments. . .

Comments (13) + TrackBacks (0) | Category: The Scientific Literature

June 6, 2013

The Ax At Aveo

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Posted by Derek

The failure at the FDA of Aveo's kinase inhibitor tivozanib has had the expected fallout: the company has cut over half its employees.

I cannot resist linking to Adam Feuerstein's take on this news. If there's a case against his viewpoint, I'd be glad to link to that as well. But for now:

Aveo Oncology (AVEO_) fired 140 middle and lower-level employees -- 62 percent of its workforce -- on Tuesday in order to save money to pay the salaries and bonuses of its top executives who blew up the company, decimated shareholder value and are too cowardly to accept responsibility for their incompetence.

At Aveo, accountability starts at the bottom.

Comments (27) + TrackBacks (0) | Category: Business and Markets

Today's Avandia Hearing at the FDA

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Posted by Derek

If you want to follow the blow-by-blow of today's FDA hearing on the marketing restrictions on Avandia (rosiglitazone), I can send you to Matthew Herper's Twitter feed. He has the goods.

Comments (3) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

Research Fraud at GSK Shanghai?

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Posted by Derek

Update: the story continues to develop. The scientist mentioned below, Jingwu Zang has been dismissed from GSK, and others are under investigation. The paper itself is in the process of being retracted. More here.

This is quite bad. Reports have been circulating that GlaxoSmithKline is investigating the scientists (and the results) behind this 2010 paper in Nature Medicine.

That first link from Pharmalot mentions this thread at the Chinese mitbbs.com site, and similar stuff has been showing up elsewhere. The online speculation is about Jingwu Zang (sometimes appearing as Zhang, the more common transliteration of the name), who was the lead author on the paper. Various postings (from the same person?) claim that Zang has been let go from GSK, and the Biocentury link in the first paragraph says that mail to his corresponding address bounces back.

The paper is (was?) on IL-7's role in autoimmune disease, a perfectly good topic for a drug company research group to be investigating, of course. But now we're going to have to watch to see if any retraction comes out of this - GSK doesn't have to comment on their hiring (and firing) decisions, but I hope that they wouldn't let a fraudulent Nature Medicine paper stand. That's the really disturbing thing about this situation; I'll see if I can explain what I mean.

A critic from outside the drug industry might say "So what? You people publish shady junk all the time? What's another truth-stretching paper, more or less?" Now, I resent implications like that, but at the same time, there have indeed been instances of nasty publication behavior (ghostwriting, etc.), which I deplore. But those things have been driving by the desire to increase sales of approved drugs. They come from overzealous marketing departments clawing for share, trying to get physicians to write for the company's drug over the other choices.

But the further back you go from the elbow-throwing front lines of the market, the less of that stuff you should see. The paper under scrutiny is early-stage research; it could have come from any good lab (academic or industrial) studying T-cell behavior, multiple sclerosis, or autoimmune mechanisms. Frankly, most of the shady stuff (and retractions) in this kind of work come from academia: the viciously competitive front lines of their market are publications in prestigious journals (like Nature Medicine), which directly bear on funding and tenure decisions. Drug companies have an incentive to stretch the truth about how wonderful their current drug is, not about what their scientists have discovered about biochemistry and cell biology. That doesn't bring in any money.

But what a publication like that does bring in, perhaps, is internal prestige. If you're trying to show what a big deal your particular branch of the company is, and what high-quality work they do, this would be one good way to do it. Keep in mind, publications like this are not the primary goal of people in the drug business; it's not like academia. The job of a drug company research group is to increase the number of drugs the company finds, and publishing in a good journal really doesn't have much to do with that. This publication, though, is a way of telling everyone else - other drug companies, other academic and industrial scientists, other departments and higher-ups at GSK, who may or may not know much about immunology per se, that GSK's Shanghai labs do good enough work to get it into Nature Medicine.

And while we're talking about this, let's talk about another widely-held belief about pharma research branches in China. There have, of course, been a number of these opened over the last five or ten years. And there are a lot of good scientists in China, and there are a lot of research topics that are relevant to the needs of a big drug company, so why not? But it's also widely assumed - although this is certainly not written down anywhere - that the Chinese government very much encourages big foreign companies to start such operations in China itself. If you lend your company's internationally known name to an operation in Shanghai (or wherever), if you invest in getting that site going, if you hire a big group of Chinese nationals to work there and manage things. . .well, the Chinese authorities are just going to like you more. Aren't they? And while being liked by the authorities is never a bad thing in any country in the world, particularly in a heavily regulated industry like pharmaceuticals, it is a particularly good thing in some of them.

This is an unfortunate situation. I believe very strongly in a government of laws, not of men - appropriately enough for where I work, that phrase was written by John Adams into the Constitution of Massachusetts. It's an ideal very difficult to realize, particularly since both Massachusetts and the rest of the world are stocked with human beings, but ideals are supposed to be difficult to realize. I understand that personal connections matter all over the world, and that this is by no means always a bad thing. But the bigger and broader the issues, the more important should be the rule of law.

The particular problem of multinational Chinese research institutes, which this current scandal can only worsen, is that too many people can assume that they've been built mainly to satisfy the Chinese government. They suffer, in other words, from the curse of affirmative action (and other such preference programs): the ever-present suspicion that once merit and ability are made secondary, that all bets are off. (This online debate at The Economist does a good job of airing out such concerns). In other words, the government of China could well end up accomplishing the exact reverse of what it's presumably trying to do: instead of elevating Chinese research (and researchers), it could be damaging the reputations of both.

Comments (58) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 5, 2013

Quaternary Chiral Centers Made to Order

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Posted by Derek

Chiral catalyst reactions seem to show up on both lists when you talk about new reactions: the list of "Man, we sure do need more of those" and the "If I see one more paper on that I'm going to do something reckless" list.

I sympathize with the latter viewpoint, but the former is closer to reality. What we don't need are more lousy chiral catalyst papers, though, on that I think we can all agree. So I wanted to mention a good one, from Erick Carreira's group at the ETH. They're trying something that we're probably going to be seeing more of in the future: a "dual-catalyst" approach:

In a conceptually different construct aimed at the synthesis of compounds with a pair of stereogenic centers, two chiral catalysts employed concurrently could dictate the configuration of the stereocenters in the product. Ideally, these would operate independently and set both configurations in a single transition state with minimal matched/mismatched interactions. Herein, we report the realization of this concept in the development of a method for the stereodivergent dual-catalytic α-allylation of aldehydes.

Shown is a typical reaction scheme. They're doing iridium-catalysed allylation reactions, which are already known via the work of Hartwig and others, but with a chiral catalyst to activate the nucleophilic end of the reaction and a separate one for the electrophilic end. That lets you more or less dial in the stereocenters you want in the product. It looks like the allyl alcohol need some sort of aryl group, although they can get it to work with a variety of those. The aldehyde component can vary more widely.
Allyl%20reaction.png
You'd expect a scheme like this to have some combinations that work great, but other mismatched ones that struggle a bit. But in this case the yields stay at 60 to 80%, and the ee values are >99% across the board as they switch things around, which is why we're reading this in Science rather than in, well, you can fill in the names of some other journals as well as I can. Making a quaternary chiral center next to a tertiary one in whatever configuration you want is not something you see every day.

I think that chiral multi-catalytic systems will be taking up even more journal pages than ever in the future. It really seems like a way to get things to perform, and there's certainly enough in the idea to keep a lot of people occupied for a long time. Those of us doing drug discovery should resist the urge to flip the pages too quickly, too, because if we really mean all that stuff about making more three-dimensional molecules, we're going to have to do better with chirality than "Run it down an SFC and throw half of it away".

Comments (13) + TrackBacks (0) | Category: Chemical News

ChemDraw on the iPad

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Posted by Derek

If you're in iPad sort of chemist (one of Baran's customers?), you may well already know that app versions of ChemDraw and Chem3D came out yesterday for that platform. I haven't tried them out myself, not (yet) being a swipe-and-poke sort of guy, but at $10 for the ChemDraw app (and Chem3D for free), it could be a good way to get chemical structures going on your own tablet.

Andre the Chemist has a writeup on his experiences here. As an inorganic chemist, he's run into difficulties with text labels, but for good ol' organic structures, things should be working fine. I'd be interested in hearing hands-on reviews of the software in the comments: how does the touch-screen interface work out for drawing? Seems like it could be a good fit. . .

Update: here's a review at MacInChem, and one at Chemistry and Computers.

Comments (14) + TrackBacks (0) | Category: Chemical News

June 4, 2013

AstraZeneca, As Expected, Pulls the Plug

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Posted by Derek

Late last year came word that the AstraZeneca/Rigel compound, fostamatinib, had failed to show any benefit versus AbbVie's Humira in the clinic. Now they've gritted their corporate teeth and declared failure, sending the whole program back to Rigel.

I've lost count of how many late-stage clinical wipeouts this makes for AZ, but it sure is a lot of them. The problem is, it's hard to say just how much of this is drug discovery itself (after all, we have brutal failure rates even when things are going well), how much of it is just random bad luck, or what might be due to something more fundamental about target and compound selection. At any rate, their CEO, Pascal Soriot, has a stark backdrop against which to perform. Odds are, things will pick up, just by random chance if by nothing else. But odds are, that may not be enough. . .

Comments (19) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

The Flip Side: Organic Chemistry That Should Be More Famous

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Posted by Derek

I see that Neil Withers is trying to start up a new discussion in that "Kudzu of Chemistry" comment thread. The main topic is what reactions and chemistry we see too much of, but he's wondering what we should see more of. It's a worthwhile question, but I wonder if it'll be hard to answer. Personally, I'd like to see more reactions that let me attach primary and secondary amines directly into unactivated alkyl CH bonds, but I'm not going to arrange my schedule around that waiting period.

So maybe we should stick with reactions (or reaction types) that have been reported, but don't seem to be used as much as they should. What are the unsung chemistries that should be more famous? What reactions have you seen that you can't figure out why no one's ever followed up on them? I'll try to add some of my own in the comments as the day goes on.

Comments (25) + TrackBacks (0) | Category: Chemical News

June 3, 2013

Chemical Biology Highlights

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Posted by Derek

Here's a worthwhile paper from Donna Huryn, Lynn Resnick, and Peter Wipf on the academic contributions to chemical biology in recent years. They're not only listing what's been done, they're looking at the pluses and minuses of going after probe/tool compounds in this setting:

The academic setting provides a unique environment distinct from traditional pharmaceutical or biotechnology companies, which may foster success and long-term value of certain types of probe discovery projects while proving unsuitable for others. The ability to launch exploratory high risk and high novelty projects from both chemistry and biology perspectives, for example, testing the potential of unconventional chemotypes such as organometallic complexes, is one such distinction. Other advantages include the ability to work without overly constrained deadlines and to pursue projects that are not expected to reap commercial rewards, criteria and constraints that are common in “big pharma.” Furthermore, projects to identify tool molecules in an academic setting often benefit from access to unique and highly specialized biological assays and/or synthetic chemistry expertise that emerge from innovative basic science discoveries. Indeed, recent data show that the portfolios of academic drug discovery centers contain a larger percentage of long-term, high-risk projects compared to the pharmaceutical industry. In addition, many centers focus more strongly on orphan diseases and disorders of third world countries than commercial research organizations. In contrast, programs that might be less successful in an academic setting are those that require significant resources (personnel, equipment, and funding) that may be difficult to sustain in a university setting. Projects whose goals are not consistent with the educational mission of the university and cannot provide appropriate training and/or content for publications or theses would also be better suited for a commercial enterprise.

Well put. You have to choose carefully (just as commercial enterprises have to), but there are real opportunities to do something that's useful, interesting, and probably wouldn't be done anywhere else. The examples in this paper are sensors of reactive oxygen species, a GPR30 ligand, HSP70 ligands, an unusual CB2 agonist (among other things), and a probe of beta-amyloid.

I agree completely with the authors' conclusion - there's plenty of work for everyone:

By continuing to take advantage of the special expertise resident in university settings and the ability to pursue novel projects that may have limited commercial value, probes from academic researchers can continue to provide valuable tools for biomedical researchers. Furthermore, the current environment in the commercial drug discovery arena may lead to even greater reliance on academia for identifying suitable probe and lead structures and other tools to interrogate biological phenomena. We believe that the collaboration of chemists who apply sound chemical concepts and innovative structural design, biologists who are fully committed to mechanism of action studies, institutions that understand portfolio building and risk sharing in IP licensing, and funding mechanisms dedicated to provide resources leading to the launch of phase 1 studies will provide many future successful case studies toward novel therapeutic breakthroughs.

But it's worth remembered that bad chemical biology is as bad as anything in the business. You have the chance to be useless in two fields at once, and bore people across a whole swath of science. Getting a good probe compound is not like sitting around waiting for the dessert cart to come - there's a lot of chemistry to be done, and some biology that's going to be tricky almost by definition. The examples in this paper should spur people on to do the good stuff.

Comments (4) + TrackBacks (0) | Category: Chemical Biology

The Current Kudzu of Chemistry?

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Posted by Derek

Chemistry, like any other human-run endeavor, goes through cycles and fads. At one point in the late 1970s, it seemed as if half the synthetic organic chemists in the world had made cis-jasmone. Later on, a good chunk of them switched to triquinane synthesis. More recently, ionic liquids were all over the literature for a while, and while it's not like they've disappeared, they're past their publishing peak (which might be a good thing for the field).

So what's the kudzu of chemistry these days? One of my colleagues swears that you can apparently get anything published these days that has to do with a BODIPY ligand, and looking at my RSS journal feeds, I don't think I have enough data to refute him. There are still an awful lot of nanostructure papers, but I think that it's a bit harder, compared to a few years ago, to just publish whatever you trip over in that field. The rows of glowing fluorescent vials might just have eased off a tiny bit (unless, of course, that's a BODIPY compound doing the fluorescing!) Any other nominations? What are we seeing way too much of?

Comments (35) + TrackBacks (0) | Category: Chemical News | The Scientific Literature