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About this Author
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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April 22, 2014

Funding Undergraduate Summer Research

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Posted by Derek

I wanted to mention another crowdfunded organic chemistry effort, this one on a small (and useful) scale. A former colleague of mine, Brent Chandler, is an assistant professor of chemistry at Illinois College, and he's working with undergraduates in organic synthesis. At the moment, he's trying to get funding for a summer undergraduate to work on a new synthesis of muscone. Synthesis of these macrocyclic musk compounds has only recently become economical at all, and prices are still high, so there's an opportunity.

I got my own start in the business as a summer undergrad back in 1981 at Hendrix College, and it was a great experience. The Indiegogo site for this effort is here. Chandler is trying to find an economical route to muscone, to train a young chemist, and to demonstrate to his institution that this can be a viable way to fund targeted research projects. We'll see how it works out!

Comments (10) + TrackBacks (0) | Category: Chemical News

April 21, 2014

Molecular Printing of Drug Molecules. Say What?

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Posted by Derek

Update: the author of this paper has appeared in the comments here (and elsewhere) saying that he's withdrawing the paper. These are apparently reviewer's comments on it, although I have no way of verifying that. Many of them don't sound like the comments I might have expected. There's more here as well.

Here we have one of the oddest papers to appear in Drug Discovery Today, which is saying something. The journal has always ranged wider than some of the others in this space, but this is the furthest afield I've seen to date. The title is "DrugPrinter: print any drug instantly", and I don't think I can do better than letting the abstract speak for itself:

In drug discovery, de novo potent leads need to be synthesized for bioassay experiments in a very short time. Here, a protocol using DrugPrinter to print out any compound in just one step is proposed. The de novo compound could be designed by cloud computing big data. The computing systems could then search the optimal synthesis condition for each bond–bond interaction from databases. The compound would then be fabricated by many tiny reactors in one step. This type of fast, precise, without byproduct, reagent-sparing, environmentally friendly, small-volume, large-variety, nanofabrication technique will totally subvert the current view on the manufactured object and lead to a huge revolution in pharmaceutical companies in the very near future.

Now, you may well read that and ask yourself "What is this DrugPrinter, and how can I get one?" But note how it's all written in the conditional - lots of woulds and coulds, which should more properly be mights and maybes. Or maybe nots. The whole thing is a fantasy of atomic-level nanotechnology, which I, too, hope may be possible at some point. But to read about the DrugPrinter, you'd think that someone's ready to start prototyping. But no one is, believe me. This paper "tells" you all the "steps" that you would need to "print" a molecule, but it leaves out all the details and all the hard parts:

Thus, if DrugPrinter can one day become a reality it will be a huge step forward in drug discovery. The operator needs only to sit down in front of a computer and draw the structure of compound, which is then inputted into the computer, and the system will automatically search by cloud computing for suitable reaction conditions between bond and bond. . .

That actually captures the tone of this paper pretty well - it exists on a slightly different plane of reality, and what it's doing in Drug Discovery Today is a real mystery, because there's not much "Today" in it, for one thing. But there's something else about it, too - try this part out and see what you think:

Thus, this novel protocol only needs one step instead of the five-to-ten steps of the current synthesis process. In actual fact, it is even better than click chemistry, with lower costs and with better precision of synthesis. A world-leading group led by Lee Cronin has made advances with the technology named ‘Chemputer’. However, it is different to our concept. We specifically address the detail of how to pick up each atom and react. We also disagree that it is possible for anyone to simply download the software (app) from the internet and use it to print one's own drug. It is not feasible and should be illegal in the future.

Some of this, naturally, can be explained by non-native English usage, although the editorial staff at DDT really should have cleaned that up a bit. But there's an underlying strain of grandiose oddness about the whole manuscript. It makes for an interesting reading experience, for sure.

The paper proposes a molding process to fit the shape of the desired target molecule, which is not prima facie a crazy idea at all (templated synthesis). But remember, we're down on the atomic scale here. The only thing to build the mold out of is more atoms, at the same scale as the material filling the mold, and that's a lot harder than any macroscale molding process that you can make analogies to. The MIP (molecularly imprinted polymer) idea is the closest real-world attempt at this sort of thing, but it's been around for quite a while now without providing a quick route into molecular assembly. There is no quick route into molecular assembly, and you're certainly

Comments (45) | Category: Chemical News | The Scientific Literature

April 17, 2014

Gitcher SF5 Groups Right Here

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Posted by Derek

I think that several of us in medicinal chemistry have been keeping our eyes out for a chance to work in a pentafluorosulfanyl (SF5) group. I know I have - I actually have a good-sized folder on the things, and some of the intermediates as well, but I've never found the right opportunity. Yeah, I know, they're big and greasy, but since when that that ever stop anyone in this business?

Well, here are are some new routes to (pentafluorosulfanyl)difluoroacetic acid, a compound that had previously only existed in a few scattered literature reports (and those from nasty chemistry). So we all have even less of an excuse to start polluting enhancing our screening collections with these things. Who's first?

Comments (16) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

April 16, 2014

The Latest Protein-Protein Compounds

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Posted by Derek

Here's a review of protein-protein interaction "hot spots" and their application to drug discovery. There have been several overviews like this over the years. This one doesn't break much new ground, but it does provide a number of recent examples, all in one place.

People approach this subject because of its intrinsic interest (how proteins interact), and in hopes of finding small molecules that can interfere. The hot spot concept meshes well with the latter - if there's some key interaction, then you have a much better chance of messing with it via a drug-like molecule, compared to the one-wrinkled-surface-approaching-another-one mode of binding. There are probably no examples at either pure end of that continuum. Alanine scanning of a protein-protein interaction will always, I think, tell you that some residues are more important than others. But are they important enough that disrupting just that one would mess up the whole binding event? And (a bigger problem) is there any reason for a small molecule to be there in the first place? That's the real kicker, because while there are probably plenty of PPIs that wouldn't take place if you jammed a 350-MW small molecule into the middle of them, there aren't as many protein surfaces offering enough binding energy for the small molecule to want to do that.

And that word "small" probably needs to be in quotation marks. One excuse for the low hit rates in screening such things has been that existing compound libraries aren't stocked with the sorts of structures that are more likely to hit. I'm not sure how valid this argument is. It's the sort of statement that's very close to tautology: the reason we didn't find any good hits in the screen is because we don't have good hit compounds - thanks! But there may well be structural biases as you go towards protein-surface binders - big lunker molecules with lots of aryl rings, if this attempt to calculate their properties is valid. Now, I don't know about your screening libraries, but the ones I've worked with already seem to have plenty of big flattish things in them already, so you still wonder a bit. But it does seem as if this area has a significantly greater chance of posing PK and formulation challenges, even if you do find something. The struggle continues.

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

April 15, 2014

Total Synthesis in Flow

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Posted by Derek

Ley%20flow.pngSteve Ley and co-workers have published what is surely the most ambitious flow-chemistry-based total synthesis ever attempted. Natural products spirodienal A and spirangien A methyl ester are prepared with almost every step (and purification) being done in flow mode.

The scheme shown (for one of the intermediates) will give you the idea. There are some batch-mode portage steps, such as 15 to 16, mainly because of extended reaction times that weren't adaptable to flow conditions. But the ones that could be adapated were, and it seems to have helped out with the supply of intermediates (which is always a tedious job in total synthesis, because you're either bored, when things are working like they always do, or pissed off, because something's gone wrong). Aldehyde 11 could be produced from 10 at a rate of 12 mmol/hour, for example.

The later steps of the synthesis tend much more towards batch mode, as you might imagine, since they're pickier (and not run as many times, either, I'll bet, compared to the number of times the earlier sequences were). Flow is perfect for those "Make me a pile of this stuff" situations. Overall, this is impressive work, and demonstrates still more chemistry that can be adapted usefully to flow conditions. Given my attitude towards total synthesis, I don't care much about spirodienal A, but I certainly do care about new ways to make new compounds more easily, and that's what this paper is really aiming for.

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

April 14, 2014

More on the Science Chemogenomic Signatures Paper

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Posted by Derek

phenol%20equil.png
This will be a long one. I'm going to take another look at the Science paper that stirred up so much comment here on Friday. In that post, my first objection (but certainly not my only one) was the chemical structures shown in the paper's Figure 2. A number of them are basically impossible, and I just could not imagine how this got through any sort of refereeing process. There is, for example, a cyclohexadien-one structure, shown at left, and that one just doesn't exist as such - it's phenol, and those equilibrium arrows, though very imbalanced, are still not drawn to scale.
subst%20align.png
Well, that problem is solved by those structures being intended as fragments, substructures of other molecules. But I'm still positive that no organic chemist was involved in putting that figure together, or in reviewing it, because the reason that I was confused (and many other chemists were as well) is that no one who knows organic chemistry draws substructures like this. What you want to do is put dashed bonds in there, or R groups, as shown. That does two things: it shows that you're talking about a whole class of compounds, not just the structure shown, and it also shows where things are substituted. Now, on that cyclohexadienone, there's not much doubt where it's substituted, once you realize that someone actually intended it to be a fragment. It can't exist unless that carbon is tied up, either with two R groups (as shown), or with an exo-alkene, in which case you have a class of compounds called quinone methides. We'll return to those in a bit, but first, another word about substructures and R groups.
THF%20R%20group.png
Figure 2 also has many structures in it where the fragment structure, as drawn, is a perfectly reasonable molecule (unlike the example above). Tetrahydrofuran and imidazole appear, and there's certainly nothing wrong with either of those. But if you're going to refer to those as common fragments, leading to common effects, you have to specify where they're substituted, because that can make a world of difference. If you still want to say that they can be substituted at different points, then you can draw a THF, for example, with a "floating" R group as shown at left. That's OK, and anyone who knows organic chemistry will understand what you mean by it. If you just draw THF, though, then an organic chemist will understand that to mean just plain old THF, and thus the misunderstanding.

If the problems with this paper ended at the level of structure drawing, which many people will no doubt see as just a minor aesthetic point, then I'd be apologizing right now. Update: although it is irritating. On Twitter, I just saw that someone spotted "dihydrophyranone" on this figure, which someone figured was close enough to "dihydropyranone", I guess, and anyway, it's just chemistry. But they don't. It struck me when I first saw this work that sloppiness in organic chemistry might be symptomatic of deeper trouble, and I think that's the case. The problems just keep on coming. Let's start with those THF and imidazole rings. They're in Figure 2 because they're supposed to be substructures that lead to some consistent pathway activity in the paper's huge (and impressive) yeast screening effort. But what we're talking about is a pharmacophore, to use a term from medicinal chemistry, and just "imidazole" by itself is too small a structure, from a library of 3200 compounds, to be a likely pharmacophore. Particularly when you're not even specifying where it's substituted and how. There are all kinds of imidazole out there, and they do all kinds of things.
four%20imidazoles.png
So just how many imidazoles are in the library, and how many caused this particular signature? I think I've found them all. Shown at left are the four imidazoles (and there are only four) that exhibit the activity shown in Figure 2 (ergosterol depletion / effects on membrane). Note that all four of them are known antifungals - which makes sense, given that the compounds were chosen for the their ability to inhibit the growth of yeast, and topical antifungals will indeed do that for you. And that phenotype is exactly what you'd expect from miconazole, et al., because that's their known mechanism of action: they mess up the synthesis of ergosterol, which is an essential part of the fungal cell membrane. It would be quite worrisome if these compounds didn't show up under that heading. (Note that miconazole is on the list twice).
other%20imidazoles.png
But note that there are nine other imidazoles that don't have that same response signature at all - and I didn't even count the benzimidazoles, and there are many, although from that structure in Figure 2, who's to say that they shouldn't be included? What I'm saying here is that imidazole by itself is not enough. A majority of the imidazoles in this screen actually don't get binned this way. You shouldn't look at a compound's structure, see that it has an imidazole, and then decide by looking at Figure 2 that it's therefore probably going to deplete ergosterol and lead to membrane effects. (Keep in mind that those membrane effects probably aren't going to show up in mammalian cells, anyway, since we don't use ergosterol that way).

There are other imidazole-containing antifungals on the list that are not marked down for "ergosterol depletion / effects on membrane". Ketonconazole is SGTC_217 and 1066, and one of those runs gets this designation, while the other one gets signature 118. Both bifonazole and sertaconazole also inhibit the production of ergosterol - although, to be fair, bifonazole does it by a different mechanism. It gets annotated as Response Signature 19, one of the minor ones, while sertaconazole gets marked down for "plasma membrane distress". That's OK, though, because it's known to have a direct effect on fungal membranes separate from its ergosterol-depleting one, so it's believable that it ends up in a different category. But there are plenty of other antifungals on this list, some containing imidazoles and some containing triazoles, whose mechanism of action is also known to be ergosterol depletion. Fluconazole, for example, is SGTC_227, 1787 and 1788, and that's how it works. But its signature is listed as "Iron homeostasis" once and "azole and statin" twice. Itraconzole is SGTC_1076, and it's also annotated as Response Signature 19. Voriconazole is SGTC_1084, and it's down as "azole and statin". Climbazole is SGTC_2777, and it's marked as "iron homeostasis" as well. This scattering of known drugs between different categories is possibly and indicator of this screen's ability to differentiate them, or possibly an indicator of its inherent limitations.

Now we get to another big problem, the imidazolium at the bottom of Figure 2. It is, as I said on Friday, completely nuts to assign a protonated imidazole to a different category than a nonprotonated one. Note that several of the imidazole-containing compounds mentioned above are already protonated salts - they, in fact, fit the imidazolium structure drawn, rather than the imidazole one that they're assigned to. This mistake alone makes Figure 2 very problematic indeed. If the paper was, in fact, talking about protonated imidazoles (which, again, is what the authors have drawn) it would be enough to immediately call into question the whole thing, because a protonated imidazole is the same as a regular imidazole when you put it into a buffered system. In fact, if you go through the list, you find that what they're actually talking about are N-alkylimidazoliums, so the structure at the bottom of FIgure 2 is wrong, and misleading. There are two compounds on the list with this signature, in case you were wondering, but the annotation may well be accurate, because some long-chain alkylimidazolium compounds (such as ionic liquid components) are already known to cause mitochondrial depolarization.

But there are several other alkylimidazolium compounds in the set (which is a bit odd, since they're not exactly drug-like). And they're not assigned to the mitochondrial distress phenotype, as Figure 2 would have you think. SGTC_1247, 179, 193, 1991, 327, and 547 all have this moeity, and they scatter between several other categories. Once again, a majority of compounds with the Figure 2 substructure don't actually map to the phenotype shown (while plenty of other structural types do). What use, exactly, is Figure 2 supposed to be?

Let's turn to some other structures in it. The impossible/implausible ones, as mentioned above, turn out to be that way because they're supposed to have substituents on them. But look around - adamantane is on there. To put it as kindly as possible, adamantane itself is not much of a pharmacophore, having nothing going for it but an odd size and shape for grease. Tetrahydrofuran (THF) is on there, too, and similar objections apply. When attempts have been made to rank the sorts of functional groups that are likely to interact with protein binding sites, ethers always come out poorly. THF by itself is not some sort of key structural unit; highlighting it as one here is, for a medicinal chemist, distinctly weird.

What's also weird is when I search for THF-containing compounds that show this activity signature, I can't find much. The only things with a THF ring in them seem to be SGTC_2563 (the complex natural product tomatine) and SGTC_3239, and neither one of them is marked with the signature shown. There are some imbedded THF rings as in the other structural fragments shown (the succinimide-derived Diels-Alder ones), but no other THFs - and as mentioned, it's truly unlikely that the ether is the key thing about these compounds, anyway. If anyone finds another THF compound annotated for tubulin folding, I'll correct this post immediately, but for now, I can't seem to track one down, even though Table S4 says that there are 65 of them. Again, what exactly is Figure 2 supposed to be telling anyone?

Now we come to some even larger concerns. The supplementary material for the paper says that 95% of the compounds on the list are "drug-like" and were filtered by the commercial suppliers to eliminate reactive compounds. They do caution that different people have different cutoffs for this sort of thing, and boy, do they ever. There are many, many compounds in this collection that I would not have bothered putting into a cell assay, for fear of hitting too many things and generating uninterpretable data. Quinone methides are a good example - as mentioned before, they're in this set. Rhodanines and similar scaffolds are well represented, and are well known to hit all over the place. Some of these things are tested at hundreds of micromolar.

I recognize that one aim of a study like this is to stress the cells by any means necessary and see what happens, but even with that in mind, I think fewer nasty compounds could have been used, and might have given cleaner data. The curves seen in the supplementary data are often, well, ugly. See the comments section from the Friday post on that, but I would be wary of interpreting many of them myself.
insolubles.png
There's another problem with these compounds, which might very well have also led to the nastiness of the assay curves. As mentioned on Friday, how can anyone expect many of these compounds to actually be soluble at the levels shown? I've shown a selection of them here; I could go on. I just don't see any way that these compounds can be realistically assayed at these levels. Visual inspection of the wells would surely show cloudy gunk all over the place. Again, how are such assays to be interpreted?

And one final point, although it's a big one. Compound purity. Anyone who's ever ordered three thousand compounds from commercial and public collections will know, will be absolutely certain that they will not all be what they say on the label. There will be many colors and consistencies, and LC/MS checks will show many peaks for some of these. There's no way around it; that's how it is when you buy compounds. I can find no evidence in the paper or its supplementary files that any compound purity assays were undertaken at any point. This is not just bad procedure; this is something that would have caused me to reject the paper all by itself had I refereed it. This is yet another sign that no one who's used to dealing with medicinal chemistry worked on this project. No one with any experience would just bung in three thousand compounds like this and report the results as if they're all real. The hits in an assay like this, by the way, are likely to be enriched in crap, making this more of an issue than ever.

Damn it, I hate to be so hard on so many people who did so much work. But wasn't there a chemist anywhere in the room at any point?

Comments (38) + TrackBacks (0) | Category: Biological News | Chemical Biology | Chemical News | The Scientific Literature

April 11, 2014

Biology Maybe Right, Chemistry Ridiculously Wrong

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Posted by Derek

Note: critique of this paper continues here, in another post.

A reader sent along a puzzled note about this paper that's out in Science. It's from a large multicenter team (at least nine departments across the US, Canada, and Europe), and it's an ambitious effort to profile 3250 small molecules in a broad chemogenomics screen in yeast. This set was selected from an earlier 50,000 compounds, since these realiably inhibited the growth of wild-type yeast. They're looking for what they call "chemogenomic fitness signatures", which are derived from screening first against 1100 heterozygous yeast strains, one gene deletion per, representing the yeast essential genome. Then there's a second round of screening against 4800 homozygous deletions strain of non-essential genes, to look for related pathways, compensation, and so on.

All in all, they identified 317 compounds that appear to perturb 121 genes, and many of these annotations are new. Overall, the responses tended to cluster in related groups, and the paper goes into detail about these signatures (and about the outliers, which are naturally interested for their own reasons). Broad pathway effects like mitrochondrial stress show up pretty clearly, for example. And unfortunately, that's all I'm going to say for now about the biology, because we need to talk about the chemistry in this paper. It isn't good.

enamine.png
phenol.pngAs my correspondent (a chemist himself) mentions, a close look at Figure 2 of the paper raises some real questions. Take a look at that cyclohexadiene enamine - can that really be drawn correctly, or isn't it just N-phenylbenzylamine? The problem is, that compound (drawn correctly) shows up elsewhere in Figure 2, hitting a completely different pathway. These two tautomers are not going to have different biological effects, partly because the first one would exist for about two molecular vibrations before it converted to the second. But how could both of them appear on the same figure?

And look at what they're calling "cyclohexa-2,4-dien-1-one". No such compound exists as such in the real world - we call it phenol, and we draw it as an aromatic ring with an OH coming from it. Thiazolidinedione is listed as "thiazolidine-2,4-quinone". Both of these would lead to red "X" marks on an undergraduate exam paper. It is clear that no chemist, not even someone who's been through second-year organic class, was involved in this work (or at the very least, involved in the preparation of Figure 2). Why not? Who reviewed this, anyway?

There are some unusual features from a med-chem standpoint as well. Is THF really targeting tubulin folding? Does adamantane really target ubiquinone biosynthesis? Fine, these are the cellular effects that they noted, I guess. But the weirdest thing on Figure 2's annotations is that imidazole is shown as having one profile, while protonated imidazole is shown as a completely different one. How is this possible? How could anyone who knows any chemistry look at that and not raise an eyebrow? Isn't this assay run in some sort of buffered medium? Don't yeast cells have any buffering capacity of their own? Salts of basic amine drugs are dosed all the time, and they are not considered - ever - as having totally different cellular effects. What a world it would be if that were true! Seeing this sort of thing makes a person wonder about the rest of the paper.

Nitro.pngMore subtle problems emerge when you go to the supplementary material and take a look at the list of compounds. It's a pretty mixed bag. The concentrations used for the assays vary widely - rapamycin gets run at 1 micromolar, while ketoconazole is nearly 1 millimolar. (Can you even run that compound at that concentration? Or that compound at left at 967 micromolar? Is it really soluble in the yeast wells at such levels? There are plenty more that you can wonder about in the same way.

And I went searching for my old friends, the rhodanines, and there they were. Unfortunately, compound SGTC_2454 is 5-benzylidenerhodanine, whose activity is listed as "A dopamine receptor inhibitor" (!). But compound SGTC_1883 is also 5-benzylidenerhodanine, the same compound, run at similar concentration, but this time unannotated. The 5-thienylidenerhodanine is SGTC_30, but that one's listed as a phosphatase inhibitor. Neither of these attributions seem likely to me. There are other duplicates, but many of them are no doubt intentional (run by different parts of the team).

I hate to say this, but just a morning's look at this paper leaves me with little doubt that there are still more strange things buried in the chemistry side of this paper. But since I work for a living (dang it), I'm going to leave it right here, because what I've already noted is more than troubling enough. These mistakes are serious, and call the conclusions of the paper into question: if you can annotate imidazole and its protonated form into two different categories, or annotate two different tautomers (one of which doesn't really exist) into two different categories, what else is wrong, and how much are these annotations worth? And this isn't even the first time that Science has let something like this through. Back in 2010, they published a paper on the "Reactome" that had chemists around the world groaning. How many times does this lesson need to be learned, anyway?

Update: this situation brings up a number of larger issues, such as the divide between chemists and biologists (especially in academia?) and the place of organic chemistry in such high-profile publications (and the place of organic chemists as reviewers of it). I'll defer these to another post, but believe me, they're on my mind.

Update 2 Jake Yeston, deputy editor at Science, tells me that they're looking into this situation. More as I hear it.

Update 3: OK, if Figure 2 is just fragments, structural pieces that were common to compounds that had these signatures, then (1) these are still not acceptable structures, even as fragments, and (2), many of these don't make sense from a medicinal chemistry standpoint. It's bizarre to claim a tetrahydrofuran ring (for example) as the key driver for a class of compounds; the chance that this group is making an actual, persistent interaction with some protein site (or family of sites) is remote indeed. The imidazole/protonated imidazole pair is a good example of this: why on Earth would you pick these two groups to illustrate some chemical tendency? Again, this looks like the work of people who don't really have much chemical knowledge.

0560-0053.pngA closer look at the compounds themselves does not inspire any more confidence. There's one of them from Table S3, which showed a very large difference in IC50 across different yeast strains. It was tested at 400 micromolar. That, folks, was sold to the authors of this paper by ChemDiv, as part of a "drug-like compound" library. Try pulling some SMILES strings from that table yourself and see what you think about their drug likeness.

Comments (129) + TrackBacks (0) | Category: Chemical Biology | Chemical News | The Scientific Literature

April 1, 2014

Yeah, That Must Be It

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Posted by Derek

I'd sort of suspected this um, breakthrough, in catalysis that See Arr Oh is reporting. But how come more of my reactions don't work, eh? 'Cause there's been all kinds of crud in them, I feel pretty sure. Maybe the various crud subtypes (cruddotypes?) are canceling each other out. . .

Comments (21) + TrackBacks (0) | Category: Chemical News

March 26, 2014

A New Fluorination

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Posted by Derek

BrittonF.pngNew fluorination reactions are always welcome, and there's one out in Ang. Chem. that looks really interesting. Robert Britton's group at Simon Fraser University report using tetrabutylammonium decatungstate as a photochemistry catalyst with N-fluorobenzenesulfonimide (NFSI). This system fluorinates unsubstituted alkanes, as shown at left, and apparently tolerates several functional groups in the process.

Note that the amino acids were fluorinated as their hydrochloride salts; the free bases didn't work. There aren't any secondary or tertiary amine substrates in the paper, nor are there any heterocycles, both of which are cause to wonder whenever you see a new fluorination method. But I think I'm going to order up some tungstate, turn on the lamp, and see what I get.

Update: via Chemjobber, here's an excellent process chemistry look at scaling up a trifluoromethylation reaction.

Comments (16) + TrackBacks (0) | Category: Chemical News

March 24, 2014

Nitrogen Heterocycles Ahoy

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Posted by Derek

Here's the sort of review that every working medicinal chemist will want to take a look at: Jeffrey Bode and graduate student Cam-Van T. Vo are looking at recent methods to prepare saturated nitrogen heterocycles. If you do drug discovery, odds are that you've worked with more piperidines, pyrrolidines, piperazines, morpholines, etc. than sticks can be shaken at. New ways to make substituted variations on these are always welcome, and it's good to see the latest work brought together into one place.

There's still an awful lot to do in this area, though. As the review mentions, a great many methods rely on nitrogen protecting groups. From personal experience, I can tell you that my heart sinks a bit when I see some nice ring-forming reaction in the literature and only then notice that the piperidine (or what have you) has a little "Ts" or "Ns" stuck to it. I know that these things can be taken off, but it's still a pain to do, and especially if you want to make a series of compounds. Protecting-group-free routes in saturated heterocyclic chemistry are welcome indeed.

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March 21, 2014

Another Use for Xenon

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Posted by Derek

An Australian reader sends this along from The Economist. Apparently xenon has been used for several years now to enhance athletic performance - who knew? Well, athletes, for one - here's an Australian cycling magazine talking about it, and Russian athletic federations have been recommending it for some time. That cycling article has a copy of a letter from the Russian Olympic committee, thanking a supplier for providing xenon to help prepare the team for the 2006 winter games in Turin.

One's first impulse would be to snort and say "Snake oil!", but one's first impulse would probably be wrong. Xenon exposure is known to set off production of the protein Hif-1-alpha, which makes sense, given that "Hif" stands for "hypoxia-inducible-factor". Increased levels are known to stimulate production of erythropoetin (a natural response to hypoxia, for sure), and xenon's effect on this whole system (demonstrated in mice and in rat cell assays) seems to be unusually long-lasting. I'd speculate that that has to do with its lipid solubility; a good strong dose of xenon probably takes longer to clear out of the tissues than you might think.

But as the Australian article goes on to argue, correctly, we don't have much reliable human data, on xenon's effects on Hif-1A in humans, on the corresponding increase in EPO, and on whether those increases are enough to really affect performance. A placebo effect would need to be ruled out, at the very least. It's also not a banned substance by the World Anti-Doping Agency (and banning it might be tricky), so athletes competing with it are not in violation of any rules. Given that xenon is already of medical interest for preventing hypoxia-related injury, I'll bet that it won't be going away any time soon.

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March 20, 2014

Small Molecule Chemistry's "Limited Utility"?

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Posted by Derek

Over at LifeSciVC, guest blogger Jonathan Montagu talks about small molecules in drug discovery, and how we might move beyond them. Many of the themes he hits have come up around here, understandably - figuring why (and how) some huge molecules manage to have good PK properties, exploiting "natural-product-like" chemical space (again, if we can figure out a good way to do that), working with unusual mechanisms (allosteric sites, covalent inhibitors and probes), and so on. Well worth a read, even if he's more sanguine about structure-based drug discovery than I am. Most people are, come to think of it.

His take is very similar to what I've been telling people in my "state of drug discovery" presentations (at Illinois, most recently) - that we medicinal chemists need to stretch our definitions and move into biomolecule/small molecule hybrids and the like. These things need the techniques of organic chemistry, and we should be the people supplying them. Montagu goes even further than I do, saying that ". . .I believe that small molecule chemistry, as traditionally defined and practiced, has limited utility in today’s world." That may or may not be correct at the moment, but I'm willing to bet that it's going to become more and more correct in the future. We should plan accordingly.

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March 19, 2014

More Things Synthetic Chemists Hate

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Posted by Derek

I enjoyed this post over at Synthetic Remarks on "Five things synthetic chemists hate". And I agree; I hate all of 'em, too. Allow me to add a few to the list:

1. The Mysterious Starting Material. How many times have you looked through an experimental section only to see a synthesis start cold, from a non-commercial compound whose preparation isn't given, or even referenced? One that doesn't seem to have any foundation anywhere else in the literature, either? I think that this is a bit more common in the older literature, but it shouldn't be happening anywhere.

2. It Works on Benzaldehyde; What More Do You Want? What about those new method papers that include a wide, diverse array of examples showing how versatile the new reaction is - but when you look at the list, you realize that it's full of things like cyclohexanone, benzaldehyde. . .and then 4-methylcyclohexanone, p-fluorobenzaldehyde, and so on? Turns out that the reaction lands flat on its nose, stretched out on the sand if there's a basic amine within five hundred yards. But you have to find that out for yourself. It ain't in the text.

3. The Paper Chase. In these days of humungous supplementary info files, what excuse is there to write a paper where all the reactions use one particular reagent - and then send people back to your previous paper to learn how to make it? Sure, reference yourself. But don't march everyone back to a whole other experimental. Are authors getting some sort of nickel-a-page-view deal from the publishers now that I haven't heard about?

4. If I Don't See It, It Isn't There. When I review papers, one of the things I end up dinging people about, more than anything else, is the reluctance to cite relevant literature. In some cases, it's carelessness, but in others, well. . .everyone's seen papers that basically rework someone else's reaction without ever citing the original. And in these days of modern times, as the Firesign Theatre guys used to say, what excuse is there?

5. Subtle Is the Lord. Once in a while, you find an experimental writeup that makes you wrinkle your brow and wonder if someone's pulling your leg. The reaction gets run at -29 degrees C, for 10.46 hours, whereupon it's brought up to -9 and quenched with pH 7.94 buffer solution. That kind of thing. If you're going to put that Proustian level of detail in there, you'd better have a reason (Proust did). No one just stumbles into conditions like that - what happened when you ran your reaction like a normal human, instead of like Vladimir Nabokov on Adderall?

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March 17, 2014

What If Total Syntheses Had Only 25 Steps to Work In?

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Posted by Derek

Via the Baran lab's Twitter feed, here's a provocative article on whether total organic synthesis has a place in the modern world or not.

One may wonder why this situation has passed undisputed for such a long time. Currently however, wide parts of the chemical community look upon total synthesis as a waste of time, resources and talents. Behind the scene, it may even be argued that the obsession to synthesize almost any natural product irrespective of its complexity and practical importance has blocked the development of other more relevant fields. Therefore, it is high time to consider a reorientation of the entire discipline

That's a bit of a straw man in that paragraph, and I have to note it, even though I do feel odd sticking up for total synthesis (about which I've been pretty caustic myself, for many years now.). I don't think that there's been an "obsession to synthesize almost any natural product", although it's true that many new synthetic methods have used some natural product or another as demonstration pieces. But the author, Johann Mulzer, came out of the Corey group in the old days, and has spent his career doing total synthesis, so he's speaking from experience here.

He goes on to argue that the field does have a place, but that it had better shape up. Short syntheses have to take priority over "first syntheses", because (let's face it), just about anything can be made if you're willing to throw enough time, money, and postdocs at it. The paper is full of examples from Mulzer's own career (and others'), and if you read it carefully, you'll see some unfavorable contrasts drawn to some Nicolaou syntheses. He finishes up:

In conclusion, this article tries to show how various strategies may be used to streamline and to shorten otherwise long synthetic routes to complex target molecules. The reader may get the impression that it pays very well to think intensively about cascade reactions, intramolecular cycloadditions, suitable starting materials and so on, instead of plunging into a brute-force and therefore mostly inefficient sequence. After all, there is an iron maxim: if a target cannot be reached within, say, 25 steps, it is better to drop it. For what you will get is a heroic synthesis, at best, but never an efficient one.

A 25-step limit would chop an awful lot out of the synthetic literature, wouldn't it? But it's not fair to apply that retrospectively. What if we apply it from here on out, though? What would the total synthetic landscape look like then?

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March 7, 2014

Some New Reviews

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Posted by Derek

Walensky and Bird have a Miniperspective out in J. Med. Chem. on stapled peptides, giving advice on how to increase one's chances of success in the area. Worth checking out, unless you're at Genentech or WEHI, of course. The authors might say that it's especially worth reading in those cases, come to think of it. I await the day when this dispute gets resolved, although a lot of people awaited the day that the nonclassical carbocation controversy got resolved, too, and look how long that took.

And in Science, Tehshik Yoon has a review on visible-light catalyzed photochemistry. I like these reactions a lot, and have run a few myself. The literature has been blowing up all over the place in this field, and it's good to have an overview like this to keep things straight.

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A Structure From the Molecular Sponge

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Posted by Derek

There's an interesting report from the Buchwald group using the Fujita "molecular sponge" crystallography technique. The last report on this was a correction, amid reports that the method was not as widely applicable as had been hoped, so I'm very happy to see it being used here.

They're revising the structure of a new reagent (from the Lu and Shen groups in Shanghai) for introducing the SCF3 group. It was proposed to be a hypervalent iodine (similar to other reagents in this class), but Buchwald's group found some NMR data and reactivity trends that suggested the structure might be in the open form, rather than the five-membered iodine ring one.

Soaking this reagent into the MOF crystal provided a structure, although if you read the supporting information, it wasn't easy. The compound was still somewhat disordered in the MOF lattice, and there were still nitrobenzene and cyclohexane solvent molecules present. The SCF3 reagent showed up in two crystallographically independent sites, one of them associated with residual nitrobenzene. After a good deal of work, though, they did show that open-form structure was present. (The Shen et al. paper's conclusions on its synthetic uses, though, are all still valid; it's just the the structure doesn't fall into the same series as expected).

So the MOF crystallography method lives, although I've still yet to hear of it giving a structure with a nitrogen-containing compound (which rather limits its use in drug discovery work, as you might imagine).

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February 21, 2014

Making Arenes React, Via Rhodium

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Posted by Derek

Just Like Cooking has an overview of some interesting new chemistry from the Hartwig group. They're using a rhodium catalyst to directly functionalize aryl rings with silyl groups (which can be used in a number of transformations downstream). One nice thing is that the selectivities are basically the opposite of the direct borylation reactions, so this could open up some isomers that are otherwise difficult to come by.

See Arr Oh makes a good point about the paper, too - it has a lot of detail in it and a lot of information. If you check out the Supplementary Information, there are about thirty pages of further details, and about sixty pages of spectral data. I particularly like the tables of various reaction conditions, hydrogen acceptors, and ligands. The main paper shows the conditions that work the best, but this gives you a chance to see under the hood at everything else that was tried. Every new methods paper should do this - in fact, every new methods paper should be required to do this. Good stuff.

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February 17, 2014

Alan Katritzky 1928-2014

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Posted by Derek

I've received word that well-known organic chemist Alan Katritzky has passed away. He's famous for his work on the use of benzotriazole compounds, and a great deal of other heterocyclic chemistry besides (2,170 papers!)

I first heard him speak in the early 1990s at the Heterocycles Gordon Conference, back in its old location in New Hampshire. And although I 'd been warned to sit near the back of the conference room, I still wasn't ready for the. . .vigor he brought to his presentation. Katritzky had clearly honed his lecturing style in large, unamplified halls, and could be easily heard outside on the lawn. The next day, Stuart McCombie opened the morning program by thanking him for ". . .sharing with me the last secret of benzotriazole. He sprinkled some down my throat AND I NEVER NEED A MICROPHONE AGAIN!"

Katritzky was a link to another era of chemistry (he studied under Sir Robert Robinson), but he leaves behind a huge legacy of work for the modern researcher. He may well have been too productive for his accomplishments to be easily categorized, or at least not yet (those 2,170 papers. . .), but there's no doubt that his name will live on.

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February 12, 2014

The Bread Rolls of Synthesis

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Posted by Derek

Over at Colorblind Chemistry, I came across a quote from Fritz Haber, writing about his thesis work:

The thesis is miserable. One and a half years of new substances prepared like baker’s bread rolls… and in addition, lots of negative results just where I was looking for significant results, and further, results that I cannot even publish because I fear that a competent chemist will find them and prove to me that the camel is missing its humps. One learns to be modest.

Now, Haber was definitely someone to take seriously. He's showing up in "The Chemistry Book", for sure, both for his historic ammonia process and his work in chemical warfare. He was a good enough chemist to know that his doctoral work was not all that great, although he seems to have followed my own recommended path to get that degree as soon as is consistent with honor and not making enemies.

The post's author, MB, wonders what this says about organic synthesis in general. How much of it is just baking bread rolls, and how bad is that? My own take is that the sort of think that Haber was regretting is the lowest form of synthesis. We've all seen the sorts of papers - here is a heterocyclic core, of no particular interest that anyone has ever been able to show. Here it has an amine. Here are twenty-five amides of that amine. Here is our paper telling you about them. Part fourteen in a series. In six months, the sulfonamides. This sort of things gets published, when it does, in the lowest tiers of the journals, and rightly so. There's nothing wrong with it (well, not usually, although this stuff isn't always the most careful work in the world). But there's nothing right with it either. It's reference data. Someone, someday, might stumble into this area of chemical space again, and when they do, they'll find a name scratched onto the wall and below it, a yellowing pile of old spectral data.

I've wondered before about what to do with those sorts of papers. There are so many compounds in the world of organic chemistry that the marginal utility of describing new random ones, while clearly not zero, is very, very close to it, especially if they're not directed towards any known use other than to make a manuscript. So if this is what's meant by baking rolls, then it's not too useful.

But I'm a medicinal chemist. When I start working on a new hit structure, I will most likely turn around and put the biggest pan of bread rolls into the biggest oven I can find. This, though, is chemistry with a purpose - there's some activity that I'm seeking, and if cranking out compounds is the best and/or fastest way to move in on it, then crank away. I'm not going to turn that blast of analogs into a paper; most (maybe all) of them will be tested, found wanting, and make their way into our compound archives. Their marginal utility is pretty low, too, given the numbers of compounds already in there, but it's still by far the best thing to do with them. Any that show activity, though, will get more attention.

I really don't mind that aspect of the synthesis I do. Setting up a row of easy reactions is actually kind of pleasant, because I know that (1) they're likely to work, and (2) they're going to tell me something I really want to know after I send them off for testing. Maybe they aren't bread rolls after all - they're bricks, and I can just possibly build something from them.

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February 10, 2014

Today We Have Naming of Parts

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Posted by Derek

I can strongly recommend this article by Carmen Drahl in C&E News on the way that we chemists pick fights over nomenclature. She has examples of several kinds of disagreement (competing terms for the same thing, terms that overlap but are still different, competing ways to measure something in different ways, and terms that are fuzzy enough that some want to eliminate them entirely).

As several of the interviewees note, these arguments are not (always) petty, and certainly not always irrational. Humans are good at reification - turning something into a "thing". Name a concept well, and it sort of shimmers into existence, giving people a way to refer to it as if it were a solid object in the world of experience. This has good and bad aspects. It's crucial to the ability to have any sort of intellectual discussion and progress, since we have to be able to speak of ideas and other entities that are not actual physical objects. But a badly fitting name can do real harm, obscuring the most valuable or useful parts of an idea and diverting thoughts about it unproductively.

My own favorite example is the use of "agonist" and "antagonist" to describe the actions of nuclear receptor ligands. This (to my way of thinking) is not only useless, but does real harm to the thinking of anyone who approaches nuclear receptors having first learned about GPCRs. Maybe the word "receptor" never should have been used for these things in the first place, although realizing that would have required supernatural powers of precognition.

There are any number of examples outside chemistry, of course. One of my own irritants is when someone says that something has been "taken to the next level". You would probably not survive watching a sports channel if that phrase were part of a drinking game. But it presupposes that some activity comes in measurable chunks, and that everyone agrees on what order they come in. I'm reminded of the old blenders with their dials clicking between a dozen arbitrary "levels", labeled with tags like "whip", "chop", and "liquify". Meaningless. It's an attempt to quantify - to reify - what should have been a smooth rheostat knob with lines around it.

OK, I'll stop before I bring up Wittgenstein. OK, too late. But he was on to something when he told people to be careful about the way language is used, and to watch out when you get out onto the "frictionless ice" of talking about constructions of thought. His final admonition in his Tractacus Logico-Philosophicus, that if we cannot speak about something that we have to pass over it in silence, has been widely quoted and widely unheeded, since we're all sure that we can, of course, speak about what we're speaking about. Can't we?

For today's post title, see here

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February 7, 2014

Thermodynamics of Life

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Posted by Derek

Origin-of-life studies have been a feature of chemistry for a long time, and over the years some key questions have become clear. It's clear from astronomical and planetary science data that the common molecules of organic chemistry are more or less soaking the universe. Amino acids and simple carbohydrates are apparently part of the cloud of gunk that makes up a new solar system, with more forming all the time. But a major step is how (and why) molecules would have organized themselves into gradually more complex systems. Some parts of the process may have been modeled already; there are a number of interesting ways that primitive membranes might have formed, which would seem to be a necessary step in distinguishing the relatively concentrated inside of a proto-cell from the more watery outside.

But a new paper (discussed here as well) has a theory that says this might have been flat-out inevitable:

From the standpoint of physics, there is one essential difference between living things and inanimate clumps of carbon atoms: The former tend to be much better at capturing energy from their environment and dissipating that energy as heat. Jeremy England, a 31-year-old assistant professor at the Massachusetts Institute of Technology, has derived a mathematical formula that he believes explains this capacity. The formula, based on established physics, indicates that when a group of atoms is driven by an external source of energy (like the sun or chemical fuel) and surrounded by a heat bath (like the ocean or atmosphere), it will often gradually restructure itself in order to dissipate increasingly more energy. This could mean that under certain conditions, matter inexorably acquires the key physical attribute associated with life. . .

. . .“This means clumps of atoms surrounded by a bath at some temperature, like the atmosphere or the ocean, should tend over time to arrange themselves to resonate better and better with the sources of mechanical, electromagnetic or chemical work in their environments,” England explained.

Self-replication would be an excellent way of doing this, and if England is right, then the development of self-organizing and replicating systems would be "baked in" to thermodynamics under the right conditions. Combine that with the organic chemistry that seems to obtain under astrophysical conditions, and we should, in theory, not be a bit surprised to find living creatures hopping around, full of amino acids and carbohydrates, using sunlight and chemical energy to do their thing.

England's theory is still fairly speculative, but he seems to be moving right along in applying it to living systems, at least on paper. What I like about this idea is that it would seem to be testable, in both living and nonliving systems. Perhaps something can be done at the level of bacteria, yeast, or even viruses or bacteriophages. I look forward to seeing some data!

Comments (37) + TrackBacks (0) | Category: Chemical News | Life As We (Don't) Know It

February 6, 2014

On Vitamin C, And On Linus Pauling

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Posted by Derek

Well, just after blasting antioxidant supplements for cancer patients (and everyone else) comes this headline: "Vitamin C Injections Ease Ovarian Cancer Treatments". Here's the study, in Science Translational Medicine. So what's going on here?

A closer look shows that this, too, appears to fit into the reactive-oxygen-species framework that I was speaking about:

Drisko and her colleagues, including cancer researcher Qi Chen, who is also at the University of Kansas, decided that the purported effects of the vitamin warranted a closer look. They noticed that earlier trials had partially relied on intravenous administration of high doses of vitamin C, or ascorbate, whereas the larger follow-up studies had used only oral doses of the drug.

This, they reasoned, could be an important difference: ascorbate is processed by the body in different ways when administered orally versus intravenously. Oral doses act as antioxidants, protecting cells from damage caused by reactive compounds that contain oxygen. But vitamin C given intravenously can have the opposite effect by promoting the formation of one of those compounds: hydrogen peroxide. Cancer cells are particularly susceptible to damage by such reactive oxygen-containing compounds.

Drisko, Chen and their colleagues found that high concentrations of vitamin C damaged DNA and promoted cell death in ovarian cancer cells grown in culture. In mice grafted with human ovarian cancer cells, treatment with intravenous vitamin C combined with conventional chemotherapy slowed tumour growth, compared to chemotherapy treatment alone.

The concentrations attained by the intravenous route are apparently necessary to get these effects, and you can't reach those by oral dosing. This 2011 review goes into the details - i.v. ascorbate reaches at least 100x the blood concentrations provided by the maximum possible oral dose, and at those levels it serves, weirdly, as a percursor of hydrogen peroxide (and a much safer one than trying to give peroxide directly, as one can well imagine). There's a good amount of evidence from animal models that this might be a useful adjunct therapy, and I'm glad to see it being tried out in the clinic.

So does this mean that Linus Pauling was right all along? Not exactly. This post at Science-Based Medicine provides an excellent overview of that question. It reviews the earlier work on intravenous Vitamin C, and also Pauling's earlier advocacy. Unfortunately, Pauling was coming at this from a completely different angle. He believed that oral Vitamin C could prevent up to 75% of cancers (his words, sad to say). His own forays into the clinic with this idea were embarrassing, and more competently run trials (several of them) have failed to turn up any benefit. Pauling had no idea that for Vitamin C to show any efficacy, that it would have to be run up to millimolar concentrations in the blood, and he certainly had no idea that it would work by actually promoting reactive oxygen species. (He had several other mechanisms in mind, such as inhibition of hyaluronidase, which do not seem to be factors in the current studies at all). In fact, Pauling might well have been horrified. Promoting rampaging free radicals throughout the bloodstream was one of the last things he had in mind; he might have seen this as no better than traditional chemotherapy (since it's also based on a treatment that's slightly more toxic to tumor cells than it is to normal ones). At the same time, he also showed a remarkable ability to adapt to new data (or to ignore it), so he might well have claimed victory, anyway.

This brings up another topic - not Vitamin C, but Pauling himself. As I've been writing "The Chemistry Book" (coming along fine, by the way), one of the things I've enjoyed is a chance to re-evaluate some of the people and concepts in the field. And I've come to have an even greater appreciation of just what an amazing chemist Linus Pauling was. He seems to show up all over the 20th century, and in my judgment could have been awarded a second science Nobel, or part of one, without controversy. I mean, you have The Nature of the Chemical Bond (a tremendous accomplishment by itself), the prediction of noble gas fluorides as possible, the alpha-helix and beta-pleated sheet structures of proteins, the mechanism of sickle cell anemia (and the concept of a "molecular disease"), the suggestion that enzymes work by stabilizing transitions states, and more. Pauling shows up all over the place - encouraging the earliest NMR work ("Don't listen to the physicists"), taking a good cut at working out the structure of DNA, all sorts of problems. He was the real deal, and accomplished about four or five times as much as anyone would consider a very good career.

But that makes it all the more sad to see what became of him in his later years. I well remember his last hurrah, which was being completely wrong about quasicrystals, from when I was in graduate school. But naturally, I'd also heard of his relentless advocacy for Vitamin C, which gradually (or maybe not so gradually) caused people to think that he had slightly lost his mind. Perhaps he had; there's no way of knowing. But the way he approached his Vitamin C work was a curious (and sad) mixture of the same boldness that had served him so well in the past, but now with a messianic strain that would probably have proven fatal to much of his own earlier work. Self-confidence is absolutely necessary for a great scientist, but too much of it is toxic. The only way to find out where the line stands is to cross it, but you won't realize it when you have (although others will).

We remember Isaac Newton for his extraordinary accomplishments in math and physics, not for his alchemical and religious calculations (to which he devoted much time, and which shocked John Maynard Keynes when he read Newton's manuscripts). Maybe in another century or two, Pauling will be remembered for his accomplishments, rather than for the times he went off the rails.

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

January 30, 2014

The West Virginia Formaldehyde Claim Is Nonsense

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Posted by Derek

This morning I heard reports of formaldehyde being found in Charleston, West Virginia water samples as a result of the recent chemical spill there. My first thought, as a chemist, was "You know, that doesn't make any sense". A closer look confirmed that view, and led me to even more dubious things about this news story. Read on - there's some chemistry for a few paragraphs, and then near the end we get to the eyebrow-raising stuff.
4-MCHM.png
The compound that spilled was (4-methylcyclohexane)methanol, abbreviated as 4-MCHM. That's its structure over there.

For the nonchemists in the audience, here's a chance to show how chemical nomenclature works. Those lines represent bonds between atoms, and if the atom isn't labeled with its own letter, it's a carbon (this compound has one one labeled atom, that O for oxygen). These sorts of carbons take four bonds each, and that means that there are a number of hydrogens bonded to them that aren't shown. You'd add one, two, or three hydrogens as needed to each to take each one up to four bonds.

The six-membered ring in the middle is "cyclohexane" in organic chemistry lingo. You'll note two things coming off it, at opposite ends of the ring. The small branch is a methyl group (one carbon), and the other one is a methyl group subsituted with an alcohol (OH). The one-carbon alcohol compound (CH3OH) is methanol, and the rules of chemical naming say that the "methanol-like" part of this structure takes priority, so it's named as a methanol molecule with a ring stuck to its carbon. And that ring has another methyl group, which means that its position needs to be specified. The ring carbon that has the "methanol" gets numbered as #1 (priority again), so the one with the methyl group, counting over, is #4. So this compound's full name is (4-methylcyclohexane)methanol.

I went into that naming detail because it turns out to be important. This spill, needless to say, was a terrible thing that never should have happened. Dumping a huge load of industrial solvent into a river is a crime in both the legal and moral senses of the word. Early indications are that negligence had a role in the accident, which I can easily believe, and if so, I hope that those responsible are prosecuted, both for justice to be served and as a warning to others. Handling industrial chemicals involves a great deal of responsibility, and as a working chemist it pisses me off to see people doing it so poorly. But this accident, like any news story involving any sort of chemistry, also manages to show how little anyone outside the field understands anything about chemicals at all.

I say that because among the many lawsuits being filed, there are some that show (thanks, Chemjobber!) that the lawyers appear to believe that the chemical spill was a mixture of 4-methylcyclohexane and methanol. Not so. This is a misreading of the name, a mistake that a non-chemist might make because the rest of the English language doesn't usually build up nouns the way organic chemistry does. Chemical nomenclature is way too logical and cut-and-dried to be anything like a natural language; you really can draw a complex compound's structure just by reading its name closely enough. This error is a little like deciding that a hairdryer must be a device made partly out of hair.

I'm not exaggerating. The court filing, by the law firm of Thompson and Barney, says explicitly:

30. The combination chemical 4-MCHM is artificially created by combining methylclyclohexane (sic) with methanol.

31. Two component parts of 4-MCHM are methylcyclohexane and methanol which are both known dangerous and toxic chemicals that can cause latent dread disease such as cancer.

Sure thing, guys, just like the two component parts of dogwood trees are dogs and wood. Chemically, this makes no sense whatsoever. Now, it's reasonable to ask if 4-MCHM can chemically degrade to methanol and 4-methylcyclohexane. Without going into too much detail, the answer is "No". You don't get to break carbon-carbon bonds that way, not without a lot of energy. If you ran the chemical (at high temperature) through some sort of catalytic cracking reactor at an oil refinery, you might be able to get something like that to happen (although I'd expect other things as well, probably all at the same time), but otherwise, no. For the same sorts of reasons, you're not going to be able to get formaldehyde out of this compound, either, not without similar conditions. Air and sunlight and water aren't going to do it, and if bacteria and fungi metabolize it, I'd expect things like (4-methylcyclohexane)carboxaldehyde and (4-methylcyclohexane)carboxylic acid, among others. I would not expect them to break off that single-carbon alcohol as formaldehyde.
MeOH%20rxn.png
So where does all this talk of formaldehyde come from? Well, one way that formaldehyde shows up is from oxidation of methanol, as shown in that reaction (this time I've drawn in all the hydrogens). This is, in fact, one of the reasons that methanol is toxic. In the body, it gets oxidized to formaldehyde, and that gets oxidized right away to formic acid, which shuts down an important enzyme. Exposure to formaldehyde itself is a different problem. It's so reactive that most cancers associated with exposure to it are in the upper respiratory tract; it doesn't get any further.

As that methanol oxidation reaction pathway shows, the body actually has ways of dealing with formaldehyde exposure, up to a point. In fact, it's found at low levels (around 20 to 30 nanograms/milliliter) in things like tomatoes and oranges, so we can assume that these exposure levels are easily handled. I am not aware of any environmental regulations on human exposure to orange juice or freshly cut tomatoes. So how much formaldehyde did Dr. Scott Simonton find in his Charleston water sample? Just over 30 nanograms per milliliter. Slightly above the tomato-juice level (27 ng/mL). For reference, the lowest amount that can be detected is about 6 ng/mL. Update: and the amount of formaldehyde in normal human blood is about 1 microgram/mL, which is over thirty times the levels that Simonton says he found in his water samples. This is produced by normal human metabolism (enzymatic removal of methyl groups and other reactions). Everyone has it. And another update: the amount of formaldehyde in normal human saliva can easily be one thousand times that in Simonton's water samples, especially in people who smoke or have cavities. If you went thousands of miles away from this chemical spill, found an untouched wilderness and had one of its natives spit in a collection vial, you'd find a higher concentration of formaldehyde.

But Simonton is a West Virginia water quality official, is he not? Well, not in this capacity. As this story shows, he is being paid in this matter by the law firm of Thompson and Barney to do water analysis. Yes, that's the same law firm that thinks that 4-MCHM is a mixture with methanol in it. And the water sample that he obtained was from the Vandalia Grille in Charleston, the owners of which are defendants in that Thompson and Barney lawsuit that Chemjobber found.

So let me state my opinion: this is a load of crap. The amounts of formaldehyde that Dr. Simonton states he found are within the range of ozonated drinking water as it is, and just above those of fresh tomato juice. These are levels that have never been shown to be harmful in humans. His statements about cancer and other harm coming to West Virginia residents seem to me to be irresponsible fear-mongering. The sort of irresponsible fear-mongering that someone might do if they're being paid by lawyers who don't understand any chemistry and are interested in whipping up as much panic as they can. Just my freely offered opinions. Do your own research and see what you think.

Update: I see that actual West Virginia public health officials agree.

Another update: I've had people point out that the mixture that spilled may have contained up to 1% methanol. But see this comment for why this probably doesn't have any bearing on the formaldehyde issue. Update, Jan 31: Here's the MSDS for the "crude MHCM" that was spilled. The other main constituent (4-methoxymethylcyclohexane)methanol is also unlikely to produce formaldehyde, for the same reasons given above. The fact remains that the levels reported (and sensationalized) by Dr. Simonton are negligible by any standard.

Comments (111) + TrackBacks (0) | Category: Chemical News | Current Events | Press Coverage | Toxicology

January 20, 2014

A Long Fight Over Allegations of Fraud

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Posted by Derek

Here's a long article from the Raleigh News and Observer (part one and part two) on the Eaton/Feldheim/Franzen dispute in nanoparticles, which some readers may already be familiar with (I haven't covered it on the blog myself). The articles are clearly driven by Franzen's continued belief that research fraud has been committed, and the paper makes the most of it.

The original 2004 publication in Science claimed that RNA solutions could influence the crystal form of palladium nanoparticles, which opened up the possibility of applying the tools of molecular biology to catalysts and other inorganic chemistry applications. Two more papers in JACS extended this to platinum and looked at in vitro evolutionary experiments. But even by 2005, Franzen's lab (who had been asked to join the collaboration between Eaton and Feldheim, who were now at Colorado and a startup company) was generating disturbing data: the original hexagonal crystals (a very strange and interesting form for palladium) weren't pure palladium at all - on an elemental basis, they were mostly carbon. (Later work showed that they were unstable crystals of (roughly) Pd(dba)3, with solvated THF. And they were produced just as well in the negative control experiments, with no RNA added at all.

N. C. State investigated the matter, and the committee agreed that the results were spurious. But they found Feldheim guilty of sloppy work, rather than fraud, saying he should have checked things out more thoroughly. Franzen continued to feel as if justice hadn't been done, though:

In fall 2009, he spent $1,334 of his own money to hire Mike Tadych, a Raleigh lawyer who specializes in public records law and who has represented The News & Observer. In 2010, the university relented and allowed Franzen into the room where the investigation records were locked away.

Franzen found the lab notebooks, which track experiments and results. As he turned the pages, he recognized that Gugliotti kept a thorough and well-organized record.

“I found an open-and-shut case of research fraud,” Franzen said.

The aqueous solution mentioned in the Science article? The experiments routinely used 50 percent solvent. The experiments only produced the hexagonal crystals when there was a high level of solvent, typically 50 percent or more. It was the solvent creating the hexagonal crystals, not the RNA.

On Page 43 of notebook 3, Franzen found what he called a “smoking gun.”

(Graduate student Lina) Gugliotti had pasted four images of hexagonal crystals, ragged around the edges. The particles were degrading at room temperature. The same degradation was present in other samples, she noted.

The Science paper claimed the RNA-templated crystals were formed in aqueous solution with 5% THF and were stable. NC State apparently offered to revoke Gugliotti's doctorate (and another from the group), but the article says that the chemistry faculty objected, saying that the professors involved should be penalized, not the students. The university isn't commenting, saying that an investigation by the NSF is still ongoing, but Franzen points out that it's been going on for five years now, a delay that has probably set a record. He's published several papers characterizing the palladium "nanocrystals", though, including this recent one with one of Eaton and Feldheim's former collaborators and co-authors. And there the matter stands.

It's interesting that Franzen pursued this all the way to the newspaper (known when I Iived in North Carolina by its traditional nickname of the Nuisance and Disturber). He's clearly upset at having joined what looked like an important and fruitful avenue of research, only to find out - rather quickly - that it was based on sloppy, poorly-characterized results. And I think what really has him furious is that the originators of the idea (Feldheim and Eaton) have tried, all these years, to carry on as if nothing was wrong.

I think, though, that Franzen is having his revenge whether he realizes it or not. It's coming up on ten years now since the original RNA nanocrystal paper. If this work were going to lead somewhere, you'd think that it would have led somewhere by now. But it doesn't seem to be. The whole point of the molecular-biology-meets-materials-science aspect of this idea was that it would allow a wide variety of new materials to be made quickly, and from the looks of things, that just hasn't happened. I'll bet that if you went back and looked up the 2005 grant application for the Keck foundation that Eaton, Feldheim (and at the time, Franzen) wrote up, it would read like an alternate-history science fiction story by now.

Comments (14) + TrackBacks (0) | Category: Chemical News | Press Coverage | The Dark Side | The Scientific Literature

January 17, 2014

A New Olefin Coupling

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Posted by Derek

Baran%20scheme.pngThe Baran group has published a neat olefin-coupling reaction which looks like something pretty useful. Building on heteroatom/olefin couplings from Boger, Carriera, and others, they use an iron catalyst and a silane to form carbon-carbon bonds between olefins, inter- or intra-molecularly. As long as you've got one olefin with an electron-withdrawing group on it, things seem to fall into place (no homocoupling of the other olefin, for example). Update: here are more details from the Baran group blog about how this reaction came to be.

I like several things about this setup: the reagents are easy to come by, for one thing (no nine-step glovebox procedure to make the catalyst). And they've taken care to run it on larger scales (by bench standards) to see if it holds up (that reaction of 14 to 15 was done on gram scale, for example). They've also checked and found that the reaction doesn't mind if it's under nitrogen or not, and that you don't have to dry the solvents. These are exactly the questions that people ask every time a spiffy new reaction comes up, and all too often the answers are "We don't know" or "Well, yeah, about that. . ."

The only thing that worries me, looking over the tables of reactions, is that there's only one with a basic nitrogen (where 3-vinylpyridine was used). Boc-nitrogen seems to be OK, but a lot of the examples are rather alkane-ish. I've no doubt that people will be testing the limits of the system soon, because it looks like a reaction worth running.

Comments (32) + TrackBacks (0) | Category: Chemical News

January 3, 2014

Easy Aziridines

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Posted by Derek

Organic synthesis is, as many have put it, a victim of its own success. Synthetic chemists can, it's true, pretty much make whatever plausible structures you can draw on the board, or whatever product some tropical fungus or toxic sponge thinks is a good idea. But we can make those only if constraints on time and money are removed. "Give me enough postdocs and I will move the Earth".

Those aren't realistic conditions, though. There are many types of compounds, some of them quite simple, for which no good synthetic routes are known. Under infinite-postdoc conditions, many of these can be worked out for specific cases (step 43 of the total synthesis of shootmenowicene), but (and here's my industrial bias showing), a good synthetic route is one that works on a variety of substrates, with readily available reagents, in reliably useful yields, under non-strenuous conditions. We're missing a lot of those.

But it looks like one might have been crossed off the list. This paper in Science, from UT-Southwestern and Brigham Young, reports a new method to make aziridines, including NH ones, in one step under mild conditions. There are quite a few methods to make aziridines, but most of them are N-substituted, particularly N-Boc and N-tosyl. A direct reaction analogous to epoxidation to give you an NH aziridine is pretty rare, but this seems to be the answer. It's a rhodium-catalyzed route that has been applied to a range of olefins, and it looks pretty mild and pretty general.

This should simplify routes to a number of natural products with this motif, but it should also prompt some new chemistry as we get easier access to that functional group. Congratulations to the authors!

Comments (10) + TrackBacks (0) | Category: Chemical News

December 30, 2013

A Table of Smells, Stinks, And Aromas

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Posted by Derek

From Monash University comes this colorful (and doubtless extremely useful) chart of Smells of Chemistry. See if you agree with its assessments - I think it's broadly correct, but I might be a bit more descriptive in some of the boxes. Although "Unique and Unpleasant" does sum up some of them pretty well, and I do like the boxes marked "Old People", "Seaweed", and "Dead Animals".

Comments (22) + TrackBacks (0) | Category: Chemical News

December 24, 2013

A Mystery Chemistry Glassware Kit

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Posted by Derek

A reader sends along this mysterious glassware set, which was donated to a nonprofit that he's working with. They're thinking of selling it on EBay, if they can figure out how to list it and what it is.
glassware.jpg
Looking at it, the lack of ground-glass joints makes you think "diazomethane kit", but I don't think that's quite right. (What are those gas impinger tubes doing in there, for example?) Kjeldahl apparatus? I haven't seen one in so long that I'm not sure about that, either. If anyone has any ideas, please feel free to take a crack.

Comments (22) + TrackBacks (0) | Category: Chemical News

December 13, 2013

Erythropoetin From Scratch

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Posted by Derek

EPO.pngThe Danishefsky group has published their totally synthetic preparation of erythropoetin. This is a work that's been in progress for ten years now (here's the commentary piece on it), and it takes organic synthesis into realms that no one's quite experienced yet:

The ability to reach a molecule of the complexity of 1 by entirely chemical means provides convincing testimony about the growing power of organic synthesis. As a result of synergistic contributions from many laboratories, the aspirations of synthesis may now include, with some degree of realism, structures hitherto referred to as “biologics”— a term used to suggest accessibility only by biological means (isolation from plants, fungi, soil samples, corals, or microorganisms, or by recombinant expression). Formidable as these methods are for the discovery, development, and manufacturing of biologics, one can foresee increasing needs and opportunities for chemical synthesis to provide the first samples of homogeneous biologics. As to production, the experiments described above must be seen as very early days. . .

I can preach that one both ways, as the old story has it. I take the point about how synthesis can provide these things in more homogeneous form than biological methods can, and it can surely provide variations on them that biological systems aren't equipped to produce. At the same time, I might put my money on improving the biological methods rather than stretching organic synthesis to this point, at least in its present form. I see the tools of molecular biology as hugely powerful, but in need of customization, whereas organic synthesis can be as custom as you like, but can (so far) only reach this sort of territory by all-out efforts like Danishefsky's. In other words, I think that molecular biology has to improve less than organic chemistry has to get the most use out of such molecules.

That said, I think that the most impressive part of this impressive paper is the area where we have the fewest molecular biology tools: the synthesis of the polysaccharide side chains. Assembling the peptide part was clearly no springtime stroll (and if you read the paper, you find that they experienced the heartbreak of having to go back and redesign things when the initial assembly sequence failed). But polyglycan chemistry has been a long-standing problem (and one that Danishefsky himself has been addressing for years). I think that chemical synthesis really has a much better shot at being the method of choice there. And that should tell you what state the field is in, because synthesis of those things can be beastly. If someone manages to tame the enzymatic machinery that produces them, that'll be great, but for now, we have to make these things the organic chemistry way when we dare to make them at all.

Comments (36) + TrackBacks (0) | Category: Chemical Biology | Chemical News

Free Chemical Patent Searching

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Posted by Derek

Here's some good news for open (free) access to chemical information. A company called SureChem was trying to make a business out of chemical patent information, but had to fold. They've donated their database to the EMBL folks, and now we have SureChEMBL. At the moment, that link is taking me to the former SureChem site, but no doubt that's changing shortly.

This will give access to millions of chemical structures in patents, a resource that's been hard to search without laying out some pretty noticeable money. This isn't just the database dump, either - the software has been donated, too, so things will stay up to date:

SureChEMBL takes feeds of full text patents, identifies chemical objects from either the in-line text or from images and adds 2-D chemical structures. This is then loaded into a database and is searchable by chemical structure, so you can do substructure, similarity searching and so forth - all the good things you'd expect from a chemical database. This chemical search functionality is unavailable from the public, published patent documents, and is really essential for anyone seriously using the patent literature. Oh, and the system does this live, so as patents are published, they are processed and added to the system - the delay between publication and structures being available in SureChEMBL is about a day when converted from text, and a few days when converted from image sources.

Chemical Abstracts, Reaxsys, and the others in that business should take note: if they want people to keep paying for their systems, they'll need to keep providing more value for the money. Good news all around.

Comments (11) + TrackBacks (0) | Category: Chemical News | Patents and IP

December 12, 2013

Tiny Details, Not So Tiny

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Posted by Derek

Chemjobber has a good post on a set of papers from Pfizer's process chemists. They're preparing filibuvir, and a key step along the way is a Dieckmann cyclization. Well, no problem, say the folks who've never run one of these things - just hit the diester compound with some base, right?

But which base? The example in CJ's post is a good one to show how much variation you can get in these things. As it turned out, LiHMDS was the base of choice, much better than NaHMDS or KHMDS. Potassium t-butoxide was just awful. But the hexamethyldisilazide was even much better than LDA, and those two are normally pretty close. But there were even finer distinctions to be made: it turned out that the reaction was (reproducibly) slightly better or slightly worse with LiHMDS from different suppliers. The difference came down to two processes used to prepare the reagent - via n-BuLi or via lithium metal, and the Pfizer team still isn't sure what the difference is that's making all the difference (see the link for more details).

That's pure, 100-proof process chemistry for you, chasing down these details. It's a good thing for people who don't do that kind of work at all, though, to read some of these papers, because it'll give you an appreciation of variables that otherwise you might not think of at all. When you get down to it, a lot of our reactions are balancing on some fairly wobbly tightropes strung across the energy-surface landscape, and it doesn't take much of a push to send them sliding off in different directions. Choice of cation, of Lewis acid, of solvent, of temperature, order of addition - these and other factors can be thermodynamic and kinetic game-changers. We really don't know too many details about what happens in our reaction flasks.

And a brief med-chem note, for context: filibuvir, into which all this work was put, was dropped from development earlier this year. Sometimes you have to do all the work just to get to the point where you can drop these things - that's the business.

Comments (8) + TrackBacks (0) | Category: Chemical News | Infectious Diseases

December 11, 2013

Best Chem-Blog Posts of 2013