About this Author
College chemistry, 1983
The 2002 Model
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: email@example.com
August 27, 2014
Here is the updated version of the "smallest drugs" collection that I did the other day. Here are the criteria I used: the molecular weight cutoff was set, arbitrarily, at aspirin's 180. I excluded the inhaled anaesthetics, only allowing things that are oils or solids in their form of use. As a small-molecule organic chemist, I only allowed organic compounds - lithium and so on are for another category. And the hardest one was "Must be in current use across several countries". That's another arbitrary cutoff, but it excludes pemoline (176), for example, which has basically been removed from the market. It also gets rid of a lot of historical things like aminorex. That's not to say that there aren't some old drugs on the remaining list, but they're still in there pitching (even sulfanilamide, interestingly). I'm sure I've still missed a few.
What can be learned from this exercise? Well, take a look at those structures. There sure are a lot of carboxylic acids and phenols, and a lot more sulfur than we're used to seeing. And pretty much everything is polar, very polar, which makes sense: if you're down in this fragment-sized space, you've got to be making some strong interactions with biological targets. These are fragments that are also drugs, so fragment-based drug discovery people may find this interesting as the bedrock layer of the whole field.
Some of these are pretty specialized and obscure - you're only going to see pralidoxime if you have the misfortune to be exposed to nerve gas, for example. But there are some huge, huge compounds on the list, too, gigantic sellers that have changed their whole therapeutic areas and are still in constant use. Metformin alone is a constant rebuke to a lot of our med-chem prejudices: who among us, had we never heard of it, would not have crossed it off our lists of screening hits? So give these small things a chance, and keep an open mind. They're real, and they can really be drugs.
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August 13, 2014
Well, the Discovery Channel has Shark Week, and apparently I have Sulfur Week going on around here. Or maybe it's Scripps Week (or Angewandte Chemie week), because here's the other paper from the Sharpless and Fokin labs on their new sulfonyl fluoride/sulfate ester chemistry. This is the extension to polymers: if you take a scaffold that has two of the sulfonyl fluoride esters on it, and react that with another OTMS-bearing monomer, you get a rapid and clean polymerization to a polysulfate.
This is a structural class that has been only lightly investigated, because of synthetic difficulties, but it's now wide open. You don't often get to see a whole new area appear like this. It'll be interesting to see what properties these have as bulk materials, when spun into fibers, and so on. And since it's polymer chemistry, the only way to find these things out is to make them and see what you get. Right off, they look like more chemically resistant forms of polycarbonates, which would surely find some use, but there are probably many other uses waiting out there as well.
The broader point made by Sharpless in this paper and the previous one is that sulfates are under-used and under-explored as functional groups. I suspect that most organic chemists will have encountered only dimethyl sulfate in their careers, and that one is hardly representative of a whole universe of compounds. Biological molecules get sulfated around their edges in vivo, but I don't think that the disulfate esters are used biologically at all (anyone know of any examples?) There must be a good reason for that, but I certainly don't know what it is. (Frank Westheimer's classic "Why Nature Chose Phosphate" is, as always, a good read in this area, but I don't think he considers sulfates in that paper). A more recent overview of the phosphorylation landscape also doesn't mention sulfates as an alternative, either. Phosphates clearly won out in the early days of biochemistry, but I don't know if that was all due to better thermodynamics, or availability (or both).
But as for organic synthesis, we can deal with all sorts of energy barriers, so there's no reason for us not to get some use out of sulfates. We just have to learn what they can do.
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The Baran group has a good method out in Angewandte on preparing sulfinates. That's a class of compound that, until recently years, not too many people have cared about - partly because they're generally not a lot of fun to make. The sulfinate acid oxidation state does not appear to be a happy one. Reductive routes exist down from the sulfonic end, but they're not reliable, and oxidations often don't stop at this state on the way up, either. Back in my sulfone/sulfoxide days in the early 1990s, I used to prepare sulfinate salts from organolithiums or Grignard reagents by bubbling in sulfur dioxide. And while that works (although not all the time), it's not that wonderful a route, either. Just thinking about it, I can taste the swampy, choking vapors coming out of the saturated solution at the end of the reaction.
I was making sulfinate esters to prepare chiral sulfoxides, which was one of the main reasons anyone would visit that functional group in synthesis. But since then it's been appreciated that sulfinates are excellent radical precursors, allowing for some very useful carbon-carbon bond-forming reactions. And that's what this new paper provides: a way to produce sulfinates straight from a wide variety of carboxylic acids by using modified Barton chemistry. The paper shows several otherwise-nearly-impossible reagents (like N-Boc azetidine-3-sulfinate), and also shows how these things will step in and staple onto heterocyclic rings directly through the radical reaction.
Their prime example is a recently reported isostere for a t-butyl group, the trifluoromethylcyclopropyl. That's a hindered beast, so many routes that you might think of to use it are going to be troublesome, but the radical reaction works quite well. I think that medicinal chemists are going to be particularly interested in this reaction, since we're so often functionalizing hetercyclic rings, and we'd like to be able to quickly expand an SAR series by sticking one group after another onto the same substrate. This sort of C-H functionalization is not something you'd think of if you're just running over the classic reactions in your head, but everyone should start adding it to their mental lists.
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August 12, 2014
I see from See Arr Oh's Twitter feed (from the ACS meeting in San Francisco) that he's attending a talk on macrocycles (and how some of them have bizarrely good PK and other properties. The speaker suggested a "Rule of 10" for orally available macrocycles: ring size greater than 10, molecular weight under 1000, and clogP around 10. That's quite a set.
The problem is, I'll bet that the percentage of reasonable-looking compounds that fit those criteria but are actually orally active is quite small. Probably significantly smaller than the percentage of reasonable-looking compounds that fit the Lipinski Ro5 criteria and behave decently. Orally-available macrocycles seem to have some sort of internal-hydrogen-bond thing going on that we don't really grasp, and you'd have to figure (hydrogen bonds being what they are) that there are far more ways to get it wrong than to get it right.
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Barry Sharpless and his group have another addition to the "click" list: the reactions of sulfonyl fluorides. They're not compounds that too many people have encountered, and you might think that they react roughly like their familiar sulfonyl chloride counterparts. But they go off in a completely different direction in many cases.
I ran into this reactivity some years ago when I was making a series of sulfone derivatives. If you try to make sulfones by adding an organolithium to a sulfonyl chloride, you're going to be disappointed. You might get a little of the chloro derivative of the lithium reagent, but you won't get any sulfones. But sulfonyl fluorides do the straight nucleophilic substitution on the sulfur and give you the desired product. Stuart McCombie, who was down the hall from me at the time, put me on to that reaction, which he'd come across some years before himself. The fluorides themselves could be prepared conveniently from KF and the sulfonyl chloride (Sharpless has a better route, I should add, one that won't displace all the other electrophiles in the substrate).
This new paper shows that sulfonyl fluorides are capable of a number of reactions that are all their own, and that this reactivity extends all the way to
sulfonyl sulfuryl fluoride itself. Inconveniently for chemists, that one's a gas, as opposed to the chloride (but that does make it widely used as a fumigant for termites). It does nothing when you expose it to water, for example, and under many conditions it's really quite unreactive. But it turns out to react with phenols very smoothly to give fluorosulfate esters whose further reactions are explored as well. The paper also mentions the uses of vinylsulfonyl fluoride, which was reported in 1979 to be a tremendous Michael acceptor (which one can believe). It may, in fact, be the Michael acceptor, reacting exhaustively with basic amines of all types within minutes. It's also shown that aryl silyl ethers react with sulfonyl fluorides very cleanly to produce unsymmetrical diarylsulfates, another class of compound that has not been well explored, probably because they're not easily prepared from sulfonyl chloride.
So there's a whole set of new reactions here, along with some nearly forgotten ones that deserved to be hauled back out into the light. The diarylsulfate click reaction alone should prove useful on tyrosines and other biological phenols, as well as providing a whole class of materials that have really never been explored, and there's a lot more here as well. I remember digging around in the older German literature on this stuff back in the early 1990s when I was doing the sulfone chemistry, but the fact that I was looking at a useful (and almost totally neglected) area of synthesis didn't register on me. At times like this, a person feels that a lot of stuff must have not registered on them over the years!
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August 7, 2014
So I go away for a few days, and people are already planning to replace me (and my colleagues) with robots? Can't turn your back on anyone in this business. What that article is talking about is the long-term dream of a "synthesis machine", a device that would take whatever structure you fed into it and start in trying to make it. No such device exists - nothing even remotely close to it exists - but there's nothing impossible about it.
A British project called Dial-a-Molecule is laying the groundwork. Led by Whitby, the £700,000 (US$1.2-million) project began in 2010 and currently runs until May 2015. So far, it has mostly focused on working out what components the machine would need, and building a collaboration of more than 450 researchers and 60 companies to help work on the idea. The hope, says Whitby, is that this launchpad will help team members to attract the long-term support they need to achieve the vision. . .
. . .Some reckon it would take decades to develop an automated chemist as adept as a human — but a less capable, although still useful, device could be a lot closer. “With adequate funding, five years and we're done,” says Bartosz Grzybowski, a chemist at Northwestern University in Evanston, Illinois, who has ambitious plans for a synthesis machine of his own.
There's a lot of room in between "as adept as a human" and "still useful", let me tell you, and that word "useful" covers a lot of ground all by itself. But I agree that there's a lot of potential here, and that we're at least getting close to the point of being able to realize some of it. But then the arguing starts. This topic came up here just recently, and has before as well. But those examples were far more simple than the Turing-machine like ideal synthesis device.
That one really is decades away, I'd say. There are a lot of problems to be dealt with. For one, you have the physical handling of reagents and reaction purification. Steve Ley's group and Tim Jamison's group are two of the best at this, and I recently had a chance to hear Jamison talk about some DARPA-funded work he's been doing on an automated platform to make simple pharmaceuticals on demand. It has taken them no small amount of work just to get the dispensing, purification, and transfer parts to mesh correctly, and that's for compounds for which defined synthetic routes have been well worked out. Throw in the problem of figuring out a good synthetic plan (among the vast number of reaction and reagent possibilities) and the problem gets wildly, exponentially more hairy.
That last link discusses some very interesting work from the Grzybowski group, who have been developing a system called Chematica. Here's the latest on that:
These demonstrations have impressed synthetic chemists, although few have had a chance to test Chematica. That is because Grzybowski is hoping to commercialize the system: he is negotiating with Elsevier to incorporate the program into Reaxys, and is working with the pharmaceutical industry to test Chematica's synthesis suggestions for biologically active, naturally occurring molecules. Grzybowski is also bidding for a grant from the Polish government, worth up to 7 million złoty (US$2.3 million), to use Chematica as the brain of a synthesis machine that can prove itself by automatically planning and executing syntheses of at least three important drug molecules.
I'll watch this with great interest, but it's worth noting that no one has yet tried to hook Grzybowski-type software with Jamison/Ley-type hardware. And that'll be a real joy to execute. This looks to an outsider (me) like one of those cases where the software folks figure that the hardware is pretty much ready to go, and the hardware folks might be figuring that the software is more or less at the late-debugging stage. I suspect that anyone thinking down those lines (and there are some quotes in that Nature article that suggest it) is in for a rude shock. The kinds of reactions that useful software would suggest will be things that no one has ever tried to automate, and the range of reagents that can be accommodated by the existing hardware may well cripple the software algorithms before they even get off the floor. There's a lot of work to be done.
My guess is that we're going to see many years of machines that can do some things in very well-defined areas, but which will prove useless (or worse) if you try to push them into unknown territory. And unknown territory is what it's all about. The article mentions the most difficult level such a machine could work at: synthetic routes where new reactions have to be invented. Don't hold your breath for that one: a machine that could work its way through the first semester of an undergraduate organic lab course would, by current standards, be a tremendous accomplishment.
But at the same time, I want to re-emphasize that there's nothing intrinsically impossible about any of this. It's just crazily hard, and will require years of machete-hacking through thickets of engineering difficulties. I think that this really is the direction the field is heading, but it's going to be a long, long road.
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July 18, 2014
There's a new report in the literature on the mechanism of thalidomide, so I thought I'd spend some time talking about the compound. Just mentioning the name to anyone familiar with its history is enough to bring on a shiver. The compound, administered as a sedative/morning sickness remedy to pregnant women in the 1950s and early 1960s, famously brought on a wave of severe birth defects. There's a lot of confusion about this event in the popular literature, though - some people don't even realize that the drug was never approved in the US, although this was a famous save by the (then much smaller) FDA and especially by Frances Oldham Kelsey. And even those who know a good amount about the case can be confused by the toxicology, because it's confusing: no phenotype in rats, but big reproductive tox trouble in mice and rabbits (and humans, of course). And as I mentioned here, the compound is often used as an example of the far different effects of different enantiomers. But practically speaking, that's not the case: thalidomide has a very easily racemized chiral center, which gets scrambled in vivo. It doesn't matter if you take the racemate or a pure enantiomer; you're going to get both of the isomers once it's in circulation.
The compound's horrific effects led to a great deal of research on its mechanism. Along the way, thalidomide itself was found to be useful in the treatment of leprosy, and in recent years it's been approved for use in multiple myeloma and other cancers. (This led to an unusual lawsuit claiming credit for the idea). It's a potent anti-angiogenic compound, among other things, although the precise mechanism is still a matter for debate - in vivo, the compound has effects on a number of wide-ranging growth factors (and these were long thought to be the mechanism underlying its effects on embryos). Those embryonic effects complicate the drug's use immensely - Celgene, who got it through trials and approval for myeloma, have to keep a very tight patient registry, among other things, and control its distribution carefully. Experience has shown that turning thalidomide loose will always end up with someone (i.e. a pregnant woman) getting exposed to it who shouldn't be - it's gotten to the point that the WHO no longer recommends it for use in leprosy treatment, despite its clear evidence of benefit, and it's down to just those problems of distribution and control.
But in 2010, it was reported that the drug binds to a protein called cereblon (CRBN), and this mechanism implicated the ubiquitin ligase system in the embryonic effects. That's an interesting and important pathway - ubiquitin is, as the name implies, ubiquitous, and addition of a string of ubiquitins to a protein is a universal disposal tag in cells: off to the proteosome, to be torn to bits. It gets stuck onto exposed lysine residues by the aforementioned ligase enzyme.
But less-thorough ubiquitination is part of other pathways. Other proteins can have ubiquitin recognition domains, so there are signaling events going on. Even poly-ubiquitin chains can be part of non-disposal processes - the usual oligomers are built up using a particular lysine residue on each ubiquitin in the chain, but there are other lysine possibilities, and these branch off into different functions. It's a mess, frankly, but it's an important mess, and it's been the subject of a lot of work over the years in both academia and industry.
The new paper has the crystal structure of thalidomide (and two of its analogs) bound to the ubiquitin ligase complex. It looks like they keep one set of protein-protein interactions from occurring while the ligase end of things is going after other transcription factors to tag them for degradation. Ubiquitination of various proteins could be either up- or downregulated by this route. Interestingly, the binding is indeed enantioselective, which suggests that the teratogenic effects may well be down to the (S) enantiomer, not that there's any way to test this in vivo (as mentioned above). But the effects of these compounds in myeloma appear to go through the cereblon pathway as well, so there's never going to be a thalidomide-like drug without reproductive tox. If you could take it a notch down the pathway and go for the relevant transcription factors instead, post-cereblon, you might have something, but selective targeting of transcription factors is a hard row to hoe.
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July 16, 2014
If you ever find yourself needing to make large cyclic peptides, you now have a new option. This paper in Organic Letters describes a particularly clean way to do it: let glutathione-S-transferase (GST) do the work for you. Bradley Pentelute's group at MIT reports that if your protein has a glutathione attached at one end, and a pentafluoroaryl Cys at the other, that GST will step in and promote the nucleophilic aromatic substitution reaction to close the two ends together.
This is an application of their earlier work on the uncatalyzed reaction and on the use of GST for ligation.. Remarkably, the GST method seems to product very high yields of cyclic peptides up to at least 40 residues, and at reasonable concentration (10 mM) of the starting material, under aqueous conditions. Cyclic peptides themselves are interesting beasts, often showing unusual properties compared to the regular variety, and this method look as it will provide plenty more of them for study.
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July 7, 2014
Catalysts are absolutely vital to almost every field of chemistry. And catalysis, way too often, is voodoo or a close approximation thereof. A lot of progress has been made over the years, and in some systems we have a fairly good idea of what the important factors are. But even in the comparatively well-worked-out areas one finds surprises and hard-to-explain patterns of reactivity, and when it comes to optimizing turnover, stability, side reactions, and substrate scope, there's really no substitute for good old empirical experimentation most of the time.
The heterogeneous catalysts are especially sorcerous, because the reactions are usually taken place on a poorly characterized particle surface. Nanoscale effects (and even downright quantum mechanical effects) can be important, but these things are not at all easy to get a handle on. Think of the differences between a lump of, say, iron and small particles of the same. The surface area involved (and the surface/volume ratio) is extremely different, just for starters. And when you get down to very small particles (or bits of a rough surface), you find very different behaviors because these things are no longer a bulk material. Each atom becomes important, and can perhaps behave differently.
Now imagine dealing with a heterogeneous catalyst that's not a single pure substance, but is perhaps an alloy of two or more metals, or is some metal complex that itself is adsorbed onto the surface of another finely divided solid, or needs small amounts of some other additive to perform well, etc. It's no mystery why so much time and effort goes into finding good catalysts, because there's plenty of mystery built into them already.
Here's a new short review article in Angewandte Chemie on some of the current attempts to lift some of the veils. A paper earlier this year in Science illustrated a new way of characterizing surfaces with X-ray diffraction, and at short time scales (seconds) for such a technique. Another recent report in Nature Communications describes a new X-ray tomography system to try to characterize catalyst particles.
None of these are easy techniques, and at the moment they require substantial computing power, very close attention to sample preparation, and (in many cases) the brightest X-ray synchrotron sources you can round up. But they're providing information that no one has ever had before about (in these examples) palladium surfaces and nanoparticle characteristics, with more on the way.
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July 1, 2014
Here's a question for those of you who've used Selectfluor (Air Products trademark), the well-known fluorinating reagent. I've had an email from someone at Sigma-Aldrich, wondering if people have noticed corrosion problems with either glass or stainless steel when usin