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: firstname.lastname@example.org
September 15, 2014
Last year I mentioned a paper that described the well-known drug tramadol as a natural product, isolated from a species of tree in Cameroon. Rather high concentrations were found in the root bark, and the evidence looked solid that the compound was indeed being made biochemically.
Well, thanks to chem-blogger Quintus (and a mention on Twitter by See Arr Oh), I've learned that this story has taken a very surprising turn. This new paper in Ang. Chem. investigates the situation more closely. And you can indeed extract tramadol from the stated species - there's no doubt about it. You can extract three of its major metabolites, too - its three major mammalian metabolites. That's because, as it turns out, tramadol is given extensively to cattle (!) in the region, so much of it that the parent drug and its metabolites have soaked into the soil enough for the African peach/pincushion tree to have taken it up into its roots. I didn't see that one coming.
The farmers apparently take the drug themselves, at pretty high dosages, saying that it allows them to work without getting tiree. Who decided it would be a good thing to feed to the cows, no one knows, but the farmers feel that it benefits them, too. So in that specific region in the north of Cameroon, tramadol contamination in the farming areas has built up to the point that you can extract the stuff from tree roots. Good grief. In southern Cameroon, the concentrations are orders of magnitude lower, and neither the farmers nor the cattle have adopted the tramadol-soaked lifestyle. Natural products chemistry is getting trickier all the time.
+ TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Natural Products
June 19, 2014
Yesterday's mention of "nightmare polyphenols" prompted a reader to ask about the one in this paper. That's it over there at the left, and yeah, that sure is a polyphenol. In fact, it's a chaetochromin, a family of mycotoxins originally isolated from moldy rice. The paper doesn't say anything about its stereochemistry, but some can be inferred from their docking models.
Their compound, denoted 4548-G05, does seem to stimulate the insulin receptor, and the list of things that do that is not a long one. A small-molecule IR compound could be quite useful in diabetes patients, of course, but no one's every been able to come up with a plausible drug candidate. Merck made a big splash back in 1999 with another fungal metabolite, L-783,281, but that never became a drug, either. This new paper advances a hypothesis of where the polyphenol binds to the extracellular domain of the insulin receptor and how it might exert its actions.
I would wonder, though, if this compound can't do the same membrane tricks as the other polyphenols mentioned yesterday. The chaetochromins seem to have a number of biological effects, which could be through all sorts of mechanisms. There's nothing to say that some of them aren't due to direct ligand-binding interactions (such as the one proposed in this latest paper), but I wouldn't rule out membrane perturbations, either. And I wouldn't bet on 4058-G05 becoming a drug, although it might lead to one eventually, after a lot of hard work.
+ TrackBacks (0) | Category: Diabetes and Obesity | Natural Products
June 18, 2014
No medicinal chemist, in my experience, is enthusiastic about polyphenol compounds. At least, not after their first experiences with them. These things are all over the natural product landscape, and many of them have biological activities, but (1) they're beastly to try to develop into drugs, and (2) no one understands very well what their targets might be or what they're doing to them.
That second part may finally be coming into the light. This paper in ACS Chemical Biology suggests that many of these compounds (our old friend resveratrol among them) may be working their way into the bilayers of cell membranes and thus affecting the activity of membrane-bound proteins. If that's true, then these compounds don't have "targets" in the usual sense of the word. They have a mechanism, but it's a broad one and likely to do all kinds of things in different cells under different conditions. We'll see if this hypothesis pans out, but it looks reasonable (and fits a lot of the hard-to-categorize facts).
+ TrackBacks (0) | Category: Natural Products
May 27, 2014
A lot of people in med-chem and chemical biology would like to have more natural-product-like features in their libraries of organic compounds. But realizing that idea is not so easy. Natural product structures, er, naturally tend to be more complex, with a lot of functionality and stereochemistry compared to the sorts of things you usually find in compound libraries. These features are usually chemically intensive, giving you a choice of a lot of structural variety or a lot of compounds, but not both at the same time.
There have been many efforts to get around this problem, among them diversity-oriented synthesis. DOS does tend to make complex compounds, but they're often out in their own area of chemical space, "unnatural products" that probably don't partake of whatever evolutionary advantages natural products have accumulated. Now there's another solution, courtesy of boronate chemisty. Martin Burke at Illinois has been working on adapting MIDA boronates to produce libraries of natural product modules and side chains, ready to be stapled on to whatever other structures you might have.
This Nature Chemistry paper has details of this approach as applied to polyene structures. There's a power-law distribution to these things that makes it all feasible:
. . .we decided to ask the question, how many bifunctional MIDA boronate building blocks would be required to make most of the polyene motifs found in nature? To find the answer, we devised a general retrosynthetic algorithm for systematically deconstructing these motifs into the minimum total number of building blocks. This analysis generated the intriguing hypothesis that the polyene motifs found in >75% of all polyene natural products can be prepared using just 12 MIDA boronate building blocks and one coupling reaction.
They've had to do a good amount of synthetic optimization to get this to work - the more straightforward conditions had compatibility problems. But it seems as if they've got some protocols now that will allow the various MIDA and pinacol boronates to work together orthogonally, and they've synthesized several natural product test cases to demonstrate. The polyenes make up between 1 and 2% of all the known natural products (>2800 of >238,000), but the idea is to extend this plan into other structural classes:
It is stimulating to consider how many building blocks would be required to access most of the remaining 99%. Although the answer to this is not yet known, the strategy demonstrated herein, that is, systematically identifying common motifs and transforming them into bifunctional building blocks compatible with iterative coupling, provides a roadmap for pursuing this problem. For example, we have identified 12 additional common structural motifs that are collectively present in more than 100,000 natural products. Half of these motifs have already been transformed into bifunctional halo MIDA boronates that are now commercially available. To achieve the same goal with some of the others will require solutions to frontier methodological problems, which include new chemistry to make and stereospecifically cross-couple Csp3 boronates.
I look forward to seeing these realized. This chemistry looks to provide a lot of interesting new compounds, and it could also answer some questions about natural products themselves. What, for example, would the screening hit rates and activity profiles be like for a large library of almost-natural products, things with the same biophysical properties and functional motifs as the rest of natural product space, but without the evolutionary fine-tuning?
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May 21, 2014
As part of the no-doubt-endless series of head-shaking natural product structures out there, allow me to present the newly described Protoaculeine B, isolated from an Okinawan marine sponge. That side chain looks as if it were inspired by listening to Philip Glass, and it fits well into the category of "I never would have made that in a million years", which so many natural products seem to occupy. But even freakier things await discovery, of that we can be sure.
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October 1, 2013
Every so often reports appear that some synthetic compound actually turns out to be a natural product. Sometimes these make very little sense, and turn out to be analytical mistakes (as with this report of nevirapine). But sometimes they're right.
This one looks as if it's right, though. Nauclea latifola, known colloquially as the "African peach", apparently has tramadol in it. That's pretty interesting, since tramadol was previously known as a synthetic opioid agonist (among other activities), used as an analgesic since the 1970s. Fittingly, preparations from this same species show up in a number of traditional medicine mixtures in West Africa, and there have also been numerous reports that extracts of the tree's roots have an analgesic effect.
This work was done through classic natural-products work: fractionate the root, test the fractions for activity in a rodent assay, home in on the active fraction and see what compounds are in it. It's always good to read about this sort of thing working - a lot of natural products were discovered this way in earlier days, but it's gotten harder over the years. Too often, there will be some extract that shows activity, which would be worth following up on if it concentrated, but none of the fractions are then particularly interesting. Here's a writeup at Chemistry World:
Our results indicate that high amounts of the analgesic drug, tramadol, can be obtained through a simple extraction procedure from Nauclea latifolia found in Cameroon or sub-Saharan areas,’ says Michel De Waard, a neuroscientist at the Université Joseph Fourier. De Waard adds that the root of the plant could be viably used as a source of tramadol because of the significantly high concentrations of the drug – over 1% of the original dry content.
The team used NMR and HRM spectroscopy, as well as x-ray crystallography, to determine the structure and confirm it as tramadol. Further spectroscopic and isotope ratio analyses confirmed that the compound extracted was indeed natural in origin, and not a by-product of cross-contamination. This unexpected discovery supports the traditional uses of N. latifolia roots in the treatment of pain; however, although other parts of the plant are also used in traditional remedies, the team found no analgesic compounds in the rest of the plant.
It's interesting that tramadol is made in such high concentrations, and it's worth speculating about what benefit the tree gets by spending that much metabolic effort. The same group that reported this isolation is now looking at the biosynthesis, and that should be worth hearing about.
Some readers, especially those outside the field, might wonder why I give this work a stamp of approval while instantly rolling my eyes at the nevirapine isolation paper. There are several reasons. One is that there are most certainly natural products that target the opioid receptors, starting with morphine and moving along from there. Natural products that potently inhibit reverse transcriptase (the target of nevirapine) are unknown to me. Nevirapine is also an unusual structure to propose as a natural product. By this point, we've isolated enough plant-derived compounds that most of the time a natural products chemist can say "Oh yeah, that's a terpenoid, looks related to such-and-such", or "Oh yeah, that's an alkaloid of the this-and-that family". Nevirapine does not fit easily into such classifications, and complete outliers like this are becoming more and more rare. If you find one, you make a big deal out of it. The last straw about the nevirapine paper was that it blithely mentioned that the compound was optically active, which was (see that earlier link for more) unlikely enough that it also would have been worth a separate paper. The fact that it was just mentioned in passing called the whole manuscript into question. The present paper suffers from none of these defects. Tramadol has certainly never been reported as a natural product, and it's interesting that it is one, but looking at its structure, you could imagine that sure, a plant could make that, one way or another.
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September 6, 2013
Acetate is used in vivo as a starting material for all sorts of ridiculously complex natural products. So here's a neat idea: why not hijack those pathways with fluoroacetate and make fluorinated things that no one's ever seen before? That's the subject of this new paper in Science, from Michelle Chang's lab at Berkeley.
There's the complication that fluoroacetate is a well-known cellular poison, so this is going to be synthetic biology all the way. (It gets processed all the way to fluorocitrate, which is a tight enough inhibitor of aconitase to bring the whole citric acid cycle to a shuddering halt, and that's enough to do the same thing to you). There a Streptomyces species that has been found to use fluoroacetate without dying (just barely), but honestly, I think that's about it for organofluorine biology.
The paper represents a lot of painstaking work. Finding enzymes (and enzyme variants) that look like they can handle the fluorinated intermediates, expressing and purifying them, and getting them to work together ex vivo are all significant challenges. They eventually worked their way up to 6-deoxyerythronolide B synthase (DEBS), which is a natural goal since it's been the target of so much deliberate re-engineering over the years. And they've managed to produce compounds like the ones shown, which I hope are the tip of a larger fluorinated iceberg.
It turns out that you can even get away with doing this in living engineered bacteria, as long as you feed them fluoromalonate (a bit further down the chain) instead of fluoroacetate. This makes me wonder about other classes of natural products as well. Has anyone ever tried to see if terpenoids can be produced in this way? Some sort of fluorinated starting material in the mevalonate pathway, maybe? Very interesting stuff. . .
+ TrackBacks (0) | Category: Chemical Biology | Chemical News | Natural Products
At C&E News, Lisa Jarvis has an excellent writeup on Warp Drive Bio and the whole idea of "cryptic natural products" (last blogged on here). As the piece makes clear, not everyone even is buying into the idea that there's a lot of useful-but-little-expressed natural product chemical matter out there, but since there could be, I'm glad that someone's looking.
Yet not everyone looked at the abundant gene clusters and saw a sea of drug candidates. The biosynthetic pathways defined by these genes are turned off most of the time. That inactivity caused skeptics to wonder how genome miners could be so sure they carried the recipes for medicinally important molecules.
Researchers pursuing genomics-based natural products say the answer lies in evolution and the environment. “These pathways are huge,” says Gregory L. Challis, a professor of chemical biology at the University of Warwick, in Coventry, England. With secondary metabolites encoded by as many as 150 kilobases of DNA, a bacterium would have to expend enormous amounts of energy to make each one.
Because they use so much energy, these pathways are turned on only when absolutely necessary. Traditional “grind and find” natural products discovery means taking bacteria out of their natural habitat—the complex communities where they communicate and compete for resources—and growing each strain in isolation. In this artificial setting, bacteria have no reason to expend energy to make anything other than what they need to survive.
“I absolutely, firmly believe that these compounds have a strong role to play in the environment in which these organisms live,” says Challis, who also continues to pursue traditional approaches to natural products. “Of course, not all bioactivities will be relevant to human medicine and agriculture, but many of them will be.”
The article also mentions that Novartis is working in this area, which I hadn't realized, as well as a couple of nonprofit groups. If there's something there, at any kind of reasonable hit rate, presumably one of these teams will find it?
+ TrackBacks (0) | Category: Biological News | Natural Products
August 2, 2013
The Baran group at Scripps has a whopper of a total synthesis out in Science. They have a route to the natural product ingenol, which is isolated from a Euphorbia species, a genus that produces a lot of funky diterpenoids. A synthetic ester of the compound as recently been approved to treat actinic keratosis, a precancerous skin condition brought on by exposure to sunlight.
The synthesis is 14 steps long, but that certainly doesn't qualify it for the "whopper" designation that I used. There are far, far longer total syntheses in the literature, but as organic chemists are well aware, a longer synthesis is not a better one. The idea is to make a compound as quickly and elegantly as possible, and for a compound like ingenol, 14 steps is pretty darn quick.
I'll forgo the opportunity for chem-geekery on the details of the synthesis itself (here's a write-up at Chemistry World). it is, of course, a very nice approach to the compound, starting from the readily available natural product (+) 3-carene, which is a major fraction of turpentine. There's a pinacol rearrangement as a key step, and from this post at the Baran group blog, you can see that it was a beast. Most of 2012 seems to have been spent on that one reaction, and that's just what high-level total synthesis is like: you have to be prepared to spend months and months beating on reactions in every tiny, picky variation that you can imagine might help.
Let me speak metaphorically, for those outside the field or who have never had the experience. Total synthesis of a complex natural product is like. . .it's like assembling a huge balloon sculpture, all twists and turns, knots and bulges, only half of the balloons are rubber and half of them are made of blown glass. And you can't just reach in and grab the thing, either, and they don't give you any pliers or glue. What you get is a huge pile of miscellaneous stuff - bamboo poles, cricket bats, spiral-wound copper tubing, balsa-wood dowels, and several barrels of even more mixed-up junk: croquet balls, doughnuts, wadded-up aluminum foil, wobbly Frisbees, and so on.
The balloon sculpture is your molecule. The piles of junk are the available chemical methods you use to assemble it. Gradually, you work out that if you brace this part over here in a cradle of used fence posts, held together with turkey twine, you can poke this part over here into it in a way that makes it stick if you just use that right-angled metal doohicky to hold it from the right while you hit the top end of it with a thrown tennis ball at the right angle. Step by step, this is how you proceed. Some of the steps are pretty obvious, and work more or less the way you pictured them, using things that are on top of one of the junk piles. Others require you to rummage through the whole damn collection, whittling parts down and tying stuff together to assemble some tool that you don't have, maybe something that no one has ever made at all.
What I like most about this new synthesis is that it's done on a real scale. LEO Pharmaceuticals is the company that sells the ingenol gel, and they're interested in seeing if there's something better. That post from Baran's group shows people holding flasks with grams of material in them. Mind you, that's what you need to get all these reactions figured out; I can only imagine how much material they must have burned off trying to get some of these steps optimized. But now that it's worked out, real quantities of analogs can be produced. Everyone who does total synthesis talks about making analogs for testing, but the follow-through is sometimes lacking. This one looks like it'll be more robust. Congratulations to everyone involved - with any luck, you'll never have to do something like this again, unless it's by choice!
Update: here's more from Carmen Drahl at C&E News.
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July 11, 2013
There hasn't been much news about Warp Drive Bio since their founding. And that founding was a bit of an unusual event all by itself, since the company was born with a Sanofi deal already in place (and an agreement for them to buy the company if targets were met). But now things seem to be happening. Greg Verdine, a founder, has announced that he's taking a three-year leave of absence from Harvard to become the company's CEO. They've also brought in some other big names, such as Julian Adams (Millennium/Infinity) to be on the board of directors.
The company has a very interesting research program: they're hoping to coax out cryptic natural products from bacteria and the like, molecules that aren't being found in regular screening efforts because the genes used in their biosynthetic pathways are rarely activated. Warp Drive's plan is to sequence heaps of prokaryotes, identify the biosynthesis genes, and activate them to produce rare and unusual natural products as drug candidates. (I'm reminded of this recent work on forcing fungi to produce odd products by messing with their epigenetic enzymes, although I'm not sure if that's what Warp Drive has in mind specifically). And the first part of that plan is what the company has been occupying itself with over the last few months:
“These are probably really just better molecules, and always were better,” he says. “The problems were that they took too long to discover and that one was often rediscovering the same things over and over again.”
Verdine explains the reason this happened is because many of the novel genes in the bacteria aren’t expressed, and remain “dark,” or turned off, and thus can’t be seen. By sequencing the microbes’ genetic material, however, Warp Drive can illuminate them, and find the roadmap needed to make a number of drugs.
“They’re there, hiding in plain sight,” Verdine says.
Over the past year and a half, Warp Drive has sequenced the entire genomes of more than 50,000 bacteria, most of which come from dirt. That library represents the largest collection of such data in existence, according to Verdine.
The entire genomes of 50,000 bacteria? I can well believe that this is the record. That is a lot of data, even considering that bacterial genomes don't run that large. My guess is that the rate-limiting step in all this is going to be a haystack problem. There are just so many things that one could potentially work on - how do you sort them out? Masses of funky natural product pathways (whose workings may not be transparent), producing masses of funky natural products, of unknown function: there's a lot to keep people busy here. But if there really is a dark-matter universe of natural products, it really could be worth exploring - the usual one certainly has been a good thing over the years, although (as noted above) it's been suffering from diminishing returns for a while.
But there's something else I wondered about when Warp Drive was founded: Verdine himself has been involved in founding several other companies, and there's another one going right here in Cambridge: Aileron Therapeutics, the flagship of the stapled-peptide business (an interesting and sometimes controversial field). How are they doing? They recently got their first compound through Phase I, after raising more money for that effort last year.
The thing is, I've heard from more than one person recently that all isn't well over there, that they're cutting back research. I don't know if that's the circle-the-wagons phase that many small companies go through when they're trying to take their first compound through the clinic, or a sign of something deeper. Anyone with knowledge, feel free to add it in the comments section. . .
Update: Prof. Verdine emails me to note that he's officially parted ways with Aileron since 2010, to avoid conflicts of interest with his other venture capital work. His lab has continued to investigate stapled peptides on their own, though.
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June 26, 2013
The topic of protein-protein inhibitor compounds has come up around here several times. It's the classic "undruggable" target, although that adjective isn't quite accurate. Let's leave it at "definitely harder than the usual stuff"; no one could argue with that.
But there's a flip side to this area that people don't think about so much. What about a compound that would make two proteins interact more tightly? A conversation with a reader of the site got me to thinking about this, and it turns out that there's a good review of the concept here, from 2012. The compounds that are known to really do this sort of thing all seem to be natural products, which I don't suppose should come as a surprise. The most well-worked-out of the group is (as some readers will have guessed) FK506 (tacrolimus). Very few drug research organizations have been brave enough to tackle a mechanism like this, so you're not going to see many examples of synthetic compounds. How small (and drug-like) a compound can be and still work through a mechanism like this is an open question.
In principle, it shouldn't be that hard a screen to run - you could imagine an assay where you watch a FRET signal hang around instead of disappearing (once you're sure that hanging all the FRET thingies off the protein partners didn't mess with the binding event, of course). You'd probably be able to see this effect by biophysical techniques as well - NMR, SPR (if you could recapitulate the protein-protein interaction with an immobilized partner on a chip), etc. You'd want a lot of structural information - seeing some sort of plausible binding surface that spans the two proteins would help to settle the nerves a bit.
You'd also want some targets, but there are probably more of them than we're used to thinking about. That's because we're don't tend to think about this mode of action at all, and if you're not keeping it in mind, you won't spot opportunities for it. The whole gain-of-function side of the business is hard to work in, for good reasons. I'm not aware of endogenous small molecules that work this way, so it's not like there are a lot of highly evolved binding pockets waiting for us to fill them. Come to think of it, I'm not aware of endogenous small molecules that work as protein-protein inhibitors, either - those processes seem to get regulated by modifications on the proteins themselves, by local concentration, or by intervention of still other proteins to rearrange binding surfaces. The scarce evolutionary record of this sort of thing might be an accident, or it might be telling us (believably) that this isn't an easy thing to do.
So I would not necessarily pin all my hopes for next year's new targets portfolio on one of these, but it would be interesting to screen and see what might turn up. Who wants to be first?
Update: here's an example from the recent literature for you!
+ TrackBacks (0) | Category: Drug Assays | Natural Products
June 25, 2013
Once in a while, you see people who've gone to the trouble of synthesizing a natural product, only to find that its structure had been incorrectly assigned. (Back in the days when structure elucidation was much harder, R. B. Woodward had this on his list of reasons to do total synthesis, although it wasn't number one).
Now there might be computational method that could flag incorrect structures earlier. This paper describes a carbon-13-NMR-based neural-network program, from a training set of 200 natural products, that seems to do a good job of flagging inconsistencies. It won't tell you that the assigned structure is right (there's probably a list of plausible fits for any given NMR), but it will speak up when something appears to be wrong.
And that's the mode I see this being used in, actually. I suspect that some groups will be motivated to go after the misassigned compounds synthetically, if they can come up with a believable alternative, in order to revise the structure. I'm not sure what happens if you put one of those South Pacific marine toxins into it, the ones that practically need a centerfold to publish their structures in a journal, but this looks like it could be a useful tool.
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June 18, 2013
Natural products come up around here fairly often, as sources of chemical diversity and inspiration. Here's a paper that combines them with another topic (epigenetics) that's been popular around here as well, even if there's some disagreement about what the word means.
A group of Japanese researchers were looking at the natural products derived from a fungus (Chaetomium indicum). Recent work has suggested that fungi have a lot more genes/enzymes available to make such things than are commonly expressed, so in this work, the team fed the fungus an HDAC inhibitor to kick its expression profile around a bit. The paper has a few references to other examples of this technique, and it worked again here - they got a significantly larger amount of polyketide products out of the fermentation, included several that had never been described before.
There have been many attempts to rejigger the synthetic machinery in natural-product-producing organisms, ranging from changing their diet of starting materials, adding environmental stresses to their culture, all the way to manipulating their actual
genomic sequences directly. This method has the advantage of being easier than most, and the number of potential gene-expression-changing compounds is large. Histone deacetylase inhibitors alone have wide ranges of selectivity against members of the class, and then you have the reverse mechanism (histone actyltranferase), methyltransferase and demethylase inhibitors, and many more. These should be sufficient to produce weirdo compounds a-plenty.
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May 31, 2013
For those who are into total synthesis of natural products, Arash Soheili has a Twitter account (Total_Synthesis) that keeps track of all the reports in the major journals. He's emailed me with a link to a searchable database of all these, which brings a lot of not-so-easily-collated information together into one place. Have a look! (Mostly, when I see these, I'm very glad that I'm not still doing them, but that's just me).
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February 26, 2013
Here's a paper at the intersection of two useful areas: natural products and fragments. Dan Erlanson over at Practical Fragments has a good, detailed look at the the work. What the authors have done is tried to break down known natural product structures into fragment-sized pieces, and cluster those together for guidance in assembling new screening libraries.
I'm sympathetic to that goal. I like fragment-based techniques, and I think that too many fragment libraries tend to be top-heavy with aromatic and heteroaromatic groups. Something with more polarity, more hydrogen-bonding character, and more three-dimensional structures would be useful, and natural products certainly fit that space. (Some of you may be familiar with a similar approach, the deCODE/Emerald "Fragments of Life", which Dan blogged about here). Synthetically, these fragments turn out to be a mixed bag, which is either a bug or a feature depending on your point of view (and what you have funding for or a mandate to pursue):
The natural-product-derived fragments are often far less complex structurally than the guiding natural products themselves. However, their synthesis will often still require considerable synthetic effort, and for widespread access to the full set of natural-product-derived fragments, the development of novel, efficient synthesis methodologies is required. However, the syntheses of natural-product-derived fragments will by no means have to meet the level of difficulty encountered in the multi-step synthesis of genuine natural products.
But take a look at Dan's post for the real downside:
Looking at the structures of some of the phosphatase inhibitors, however, I started to worry. One strong point of the paper is that it is very complete: the chemical structures of all 193 tested fragments are provided in the supplementary information. Unfortunately, the list contains some truly dreadful members; 17 of the worst are shown here, with the nasty bits shown in red. All of these are PAINS that will nonspecifically interfere with many different assays.
Boy, is he right about that, as you'll see when you take a look at the structures. They remind me of this beast, blogged about here back last fall. These structures should not be allowed into a fragment screening library; there are a lot of other things one could use instead, and their chances of leading only to heartbreak are just too high.
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February 6, 2013
My grad school work was chiral-pool synthesis; trying to make a complex natural product from carbohydrate starting materials. There was quite a bit of that around in those days, but you have to wonder about its place in the world by now. It's true that everyone likes to be able to buy their chiral centers, especially if they're from the naturally-occuring series (nobody's keen to use L-glucose as their starting material if they can avoid it!) We certainly love to do that in the drug industry, and we can often get away with such syntheses, since our compounds generally don't have too many chiral centers.
But how developed are the multicenter methods? I certainly did not enjoy manipulating the multiple chiral centers on a sugar molecule, although you can (with care and attention) do some interesting gymnastics on that framework. But I think that asymmetric synthesis, especially catalytic variations, is more widely used today to build things up, rather than starting with a lot of chirality and working it around to what you want. The synthetic difficulties of that latter method often seem to get out of hand, and the methods aren't as general as the build-up-your-chirality ones.
Is my impression correct? And if so, is this the way things should be? My tendency is to say "yes" to both questions, but I'd like to see what the general opinions are.
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December 11, 2012
Here's a funny-looking compound for you - Ivorenolide A, isolated from mahogany tree bark, it has an 18-membered ring with conjugated acetylenes in it. That makes the 3-D structure quite weird; it's nearly flat. And it has biological activity, too (immunosuppression, as measured by T-cell and B-cell proliferation assay in vitro). Got anything that looks like this in your compound libraries? Me neither.
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November 2, 2012
That title should bring in the hits. But don't get your hopes up! This is medicinal chemistry, after all.
"Can't you just put the group in your molecule that does such-and-such?" Medicinal chemists sometimes hear variations of that question from people outside of chemistry - hopeful sorts who believe that we might have some effective and instantly applicable techniques for fixing selectivity, brain penetration, toxicity, and all those other properties we're always trying to align.
Mostly, though, we just have general guidelines - not so big, not so greasy (maybe not so polar, either, depending on what you're after), and avoid a few of the weirder functional groups. After that, it's art and science and hard work. A recent J. Med. Chem. paper illustrates just that point - the authors are looking at the phenomenon of molecular promiscuity. That shows up sometimes when one compound is reasonably selective, but a seemingly closely related one hits several other targets. Is there any way to predict this sort of thing?
"Probably not", is the answer. The authors looked at a range of matched molecular pairs (MMPs), structures that were mostly identical but varied only in one region. Their data set is list of compounds in this paper from the Broad Institute, which I blogged about here. There are over 15,000 compounds from three sources - vendors, natural product collections, and Schreiber-style diversity-oriented synthesis. The MMPs are things like chloro-for-methoxy on an aryl ring, or thiophene-for-pyridyl with other substituents the same. That is, they're just the sort of combinations that show up when medicinal chemists work out a series of analogs.
The Broad data set yielded 30954 matched pairs, involving over 8000 compounds and over seven thousand different transformations. Comparing these compounds and their reported selectivity over 100 different targets (also in the original paper), showed that most of these behaved "normally" - over half of them were active against the same targets that their partners were active against. But at the other end of the scale, 829 compounds showed different activity over at least ten targets, and 126 of those compounds different in activity by fifty targets or more. 33 of them differed by over ninety targets! So there really are some sudden changes out there waiting to be tripped over; they're not frequent, but they're dramatic.
How about correlations between these "promiscuity cliff" compounds and physical properties, such as molecular weight, logP, donor/acceptor count, and so on? I'd have guessed that a change to higher logP would have accompanied this sort of thing over a broad data set, but the matched pairs don't really show that (nor a shift in molecular weight). On the other hand, most of the highly promiscuous compounds are in the high cLogP range, which is reassuring from the standpoint of Received Med-Chem Wisdom. There are still plenty of selective high-logP compounds, but the ones that hit dozens of targets are almost invariably logP > 6.
Structurally, though, no particular substructure (or transformation of substructures) was found to be associated with sudden onset of promiscuity, so to this approximation, there's no actionable "avoid sticking this thing on" rule to be drawn. (Note that this does not, to me at least, say that there are no such things are frequent-hitting structures - we're talking about changes within some larger structure, not the hits you'd get when screening 500 small rhodanine phenols or the like). In fact, I don't think the Broad data set even included many functional groups of that sort to start with.
On the basis of the data available to us, it is not possible to conclude with certainty to what extent highly promiscuous compounds engage in specific and/or nonspecific interactions with targets. It is of course unlikely that a compound might form specific interactions with 90 or more diverse targets, even if the interactions were clearly detectable under the given experimental conditions. . .
. . .it has remained largely unclear from a medicinal chemistry perspective thus far whether certain molecular frameworks carry an intrinsic likelihood of promiscuity and/or might have frequent hitter character. After all, promiscuity is determined for compounds, not their frameworks. Importantly, the findings presented herein do not promote a framework-centric view of promiscuity. Thus, for the evaluation and prioritization of compound series for medicinal chemistry, frameworks should not primarily be considered as an intrinsic source of promiscuity and potential lack of compound specificity. Rather, we demonstrate that small chemical modifications can trigger large-magnitude promiscuity effects. Importantly, these effects depend on the specific structural environment in which these modifications occur. On the basis of our analysis, substitutions that induce promiscuity in any structural environment were not identified. Thus, in medicinal chemistry, it is important to evaluate promiscuity for individual compounds in series that are preferred from an SAR perspective; observed specificity of certain analogs within a series does not guarantee that others are not highly promiscuous."
Point taken. I continue to think, though, that some structures should trigger those evaluations with more urgency than others, although it's important never to take anything for granted with molecules you really care about.
+ TrackBacks (0) | Category: Chemical News | Drug Assays | Natural Products | Toxicology
June 27, 2012
A lot of natural product structures have been misassigned over the years. In the old days, it was a wonder when you were able to assign a complex one at all. Structure determination, pre-NMR, could be an intellectual challenge at the highest level, something like trying to reconstruct a position on a chess board in the dark, based on acrostic clues in a language you don't speak. The advent of modern spectroscopy turned on the lights, which is definitely a good thing, but many people who'd made their careers under the old system missed the thrill of the old hunt when it was gone.
But even now, it's possible to get structures wrong - even with high-field 2-D NMR, even with X-ray spectroscopy. Natural products can be startlingly weird by the standards of human chemistry, and I still have a lot of sympathy for anyone who's figuring them out. My sympathy goes only so far, though.
Specifically, this case. I have to agree with the BRSM Blog, which says: "I have to say that I think I could have done a better job myself. Drunk." Think that's harsh? Check out the structures. The proposed structure had two napthalenes, with two methoxys and four phenols. But the real natural product, as it turns out, has one methoxy and one phenol. And no napthyls. And four flipping bromine atoms. Why the vengeful spirit of R. B. Woodward hasn't appeared, shooting lightning bolts and breaking Scotch bottles over people's heads, I just can't figure.
+ TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Natural Products
June 14, 2012
Via ChemJobber, here's a quote from the National Research Council's Committee on Challenges in Chemistry Graduate Education. Their report has just come out, and I agree that this should be a key point for people to ponder:
Whitesides believes that the question should be asked whether PhD theses are narrow technical presentations for jobs that no longer exist. Should U.S. graduate students be doing organic synthesis if most organic synthesis is being done in China? “That’s not to say that these aren’t really important activities, but we need to connect our investment in graduate school with what’s actually needed to give jobs to students.”
It's worth remembering that Whitesides hasn't exactly been the biggest booster of traditional organic synthesis over the years, he does have a point. This may not be the right way to look at the situation, but if it hasn't crossed your mind, you haven't thought hard enough about the issues yet. I have a couple of quick responses:
1. There are all kinds of organic synthesis. I don't think that there's much point to the human-wave-attack style of making gigantic natural products, as I've said here several times. And if there's not much point to what's considered the highest level of total synthesis, then there must really not be much to the low levels of the field. Those are the papers I'd characterize as "Here's a molecule that no one much cares about, made in a way that you'd figure would probably work, using reactions everyone already knows". But there's more to the field than that; at least, there'd better be.
2. Prof. Whitesides is exaggerating to make a point. It's not like there's no organic synthesis being done in the U.S. A lot of the stuff that's moved to China (and India) is routine chemistry that's being outsourced because it's cheap (or has been cheap, anyway). As that changes, the costs go up, and we head towards a new equilibrium. It seems beyond doubt that there are fewer people doing industrial organic chemistry than there used to be in this country, but it's not like it's only found in China (or will be).
3. That said, he's absolutely right that people need to think about where the jobs are, lest chemistry (and some other sciences) go the way of some of the humanities graduate programs. If you go off and get a doctorate in English with a dissertation on minor 18th-century poets, you're mostly qualified to teach other people about minor 18th-century poets so they can go off and write dissertations of their own. (Actually, your own work would probably have concentrated on the relation of said poets to prevailing gender norms or something, in which case I really don't see the point). We do not want to teach people to do organic chemistry if the majority of them are going to have to seek jobs teaching other people to do organic chemistry.
4. Doing that - thinking about the larger economic and scientific context - is hard. The time it takes to get a degree means that the situation could well have changed by the time a person gets out of grad school, compared with the way things looked when they made the decision to go. But this has always been the case; that's life as we know it. People have to keep their eyes open and be intelligent and flexible, because there are potential dead ends everywhere. As hard as that advice is to follow, though, I still think it's better than any sort of scheme to allocate/ration people among different fields of study. My bias against central planning isn't just philosophical; I don't see how it can possibly work, and it is very, very likely to make the situation even worse.
I'm on the train, and can't download a 120-page PDF at the moment, but I'll have a look at the report and add more thoughts as they come up.
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December 1, 2011
Readers may remember a now-retracted paper that I first blogged about here, the one that claimed to have isolated the reverse transcriptase inhibitor nevirapine as a natural product. Moreover, it claimed that the isolated material was chiral, which would have been very interesting indeed if it were true. (And, as that last post says, would have been worth making a big point of, if the authors really had understood what they were claiming).
Now a group from Manchester has weighed in on that topic. And what they find is what anyone who'd examined the field should have expected: that the nevirapine molecule, although capable of existing in two chiral forms, equilibrates between them on a time scale of seconds at room temperature. Isolating the atropisomers by standard means is not possible.
So everything about that original Tetrahedron paper was wrong; it never should have made it through the review process. And that's why I highlight such things - not to heap scorn on the original authors, which doesn't do that much good, but to heap it on the people who let such papers into print. Reviewers and editors are supposed to notice when a paper has made very unusual claims, and they're supposed to ask the authors to back them up. But the folks at Tetrahedron were asleep at the switch when this one came through. It's important for them (and other editorial staffs) not to let that happen, and it's important for a journal's readers to realize that it can.
Addendum - as an aside, I note that one of this blog's entries (the second link above) is cited in the references of this latest paper. I'm glad to be a cite-able source!
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August 26, 2011
We're going to need new antibiotics. Everyone knows this, and it's not like no one's been trying to do anything about it, either, but. . .we're still going to need more of them than we have. I'm not predicting that we're going to go all the way back to a world where young, healthy people with access to the best medical care die because they decided to play tennis without their socks on, but we're certainly in danger of a much nastier world than we have.
So I'm always interested to hear of new antibiotic discovery programs, and Merck is out with an interesting paper on theirs. They've been digging through the natural products, which have been the fount from which almost all antibiotics have sprung, and they have a new one called kibdelomycin to report. This one was dug out from an organism in a sample from the Central African Republic by a complicated but useful screening protocol, the S. aureus fitness test. This relies on 245 different engineered strains of the bacterium, each with an inducible RNAi pathway to downregulate some essential gene. When you pool these into mixed groups and grow them in the presence of test compounds (or natural product extracts) for 20 generations or so, a check of what strains have moved ahead (and fallen behind) can tell you what pathways you seem to be targeting. A key feature is that you can compare the profile you get with those of known antibiotics, so you don't end up rediscovering something (or discovering something that only duplicates what we already have anyway).
Now, that's no one's idea of a beautiful structure, although (to be fair) a lot of antibiotics have very weird structures themselves. But it's safe to say that there are some features there that could be trouble in a whole animal, such as that central keto-enol-pyrrolidone ring and the funky unsaturated system next to it. (The dichloropyrrole, though, is interestingly reminiscent of these AstraZeneca gyrase/topoisomerase antibiotic candidates, while both celestramycin and pyoluteorin have a different dichloropyrrole in them).
What kind of activity does kibdelomycin have? Well, this is where my enthusiasm cools off just a bit more. It showed up in screening with a profile similar to the coumarin antibiotics novobiocin and chlorobiocin, and sure enough, it's a topoisomerase II inhibitor. It appears to be active almost entirely on gram-positive organisms. And while there are certainly nasty gram-positive infections that have to be dealt with, I'm more encouraged when I see something that hits gram-negatives as well. They've got more complicated defenses, those guys, and they're harder to kill. It's not easy to get broad-spectrum activity when you're going after gyrase/Topo II, but the fluoroquinolones definitely manage it.
The Merck team makes much out of kibdelomycin being "the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades". And they're right that this is an accomplishment. But the kicker in that sentence is "from natural product sources". Getting gram-positive Topo II inhibitors has actually been one of the areas where synthetic compounds have had the most success. Building off the quinolones themselves has been a reasonably fruitful strategy, and a look through the literature turns up a number of other structural classes with this sort of activity (including some pretty wild ones). Not all of these are going places, but there are certainly a number of possibilities out there.
In short, if kibdelomycin weren't an odd-looking natural product, I wonder how much attention another high-molecular-weight gram-positive-only topoisomerase inhibitor would be getting, especially with only in vitro data behind it. Every little bit helps, and having a new structural class to work from is a worthwhile discovery. But one could still want (and hope) for more.
+ TrackBacks (0) | Category: Drug Assays | Infectious Diseases | Natural Products
December 15, 2010
Thanks to an email from a reader, I can bring you this very weird paper from Tetrahedron. The authors claim to have extracted a local plant and isolated nevirapine, (sold as Viramune by Boehringer Ingleheim as a reverse transcriptase inhibitor for HIV).
That's kind of odd. I'm no natural products expert, but I've sure seen a lot of them over the years, and that framework (and the N-cyclopropyl) don't look so likely to me. But hey, plants do odd things. That's not what's really puzzling about this paper. No, what's had me staring at it this morning is the claim that, in contrast to the marketed drug, this stuff is optically active nevirapine.
Say what? Try as I might, I can't see any plausible way that that's a chiral compound. The authors seem to think it is, though. They claim optical rotation, somehow, and then say that "The detailed structure and stereochemistry of compound 1 was established unambiguously by single crystal X-ray crystallography." But hold on - that's not as easy as it sounds. Getting absolute configurations from the X-ray data of light-atom-only molecules takes special efforts, and I don't see any being taken (molybdenum X-rays, direct methods, no talk of anomalous dispersion, etc.)
I'm just not willing to see that nitrogen atom as a source of chirality - if it were, shouldn't that be the focus of this whole paper? Instead, the authors just blithely tell us how neat it is that they've isolated the chiral material. In fact, they find it so neat that they tell us two times in a row:
This is a very interesting discovery that naturally occurring optically active nevirapine has been biosynthesized in the seeds of C.viscosa and the optically inactive nevirapine was designed as a selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is also a remarkable ﬁnding that the seed of C.viscosa is the source of optically active nevirapine, which was also designed and synthesized before its isolation from natural source.
This sounds like some sort of lunatic patent-busting exercise, to be honest. And it sounds as if someone doesn't know what a chiral compound is. And that whoever reviewed this for Tetrahedron was incompetent. And that the editor who let it through should be a least a little bit ashamed. Well?
+ TrackBacks (0) | Category: Infectious Diseases | Natural Products | The Scientific Literature
November 11, 2010
I've been reading an interesting new paper from Stuart Schreiber's research group(s) in PNAS. But I'm not sure if the authors and I would agree on the reasons that it's interesting.
This is another in the series that Schreiber has been writing on high-throughput screening and diversity-oriented synthesis (DOS). As mentioned here before, I have trouble getting my head around the whole DOS concept, so perhaps that's the root of my problems with this latest paper. In many ways, it's a companion to one that was published earlier this year in JACS. In that paper, he made the case that natural products aren't quite the right fit for drug screening, which fit with an earlier paper that made a similar claim for small-molecule collections. Natural products, the JACS paper said, were too optimized by evolution to hit targets that we don't want, while small molecules are too simple to hit a lot of the targets that we do. Now comes the latest pitch.
In this PNAS paper, Schreiber's crew takes three compound collections: 6,152 small commercial molecules, 2,477 natural products, and 6,623 from academic synthetic chemistry (with a preponderance of DOS compounds), for a total of 15, 252. They run all of these past a set of 100 proteins using their small-molecule microarray screening method, and look for trends in coverage and specificity. What they found, after getting rid of various artifacts, was that about 3400 compounds hit at least one protein (and if you're screening 100 proteins, that's a perfectly reasonable result). But, naturally, these hits weren't distributed evenly among the three compound collections. 26% of the academic compounds were hits, and 23% of the commercial set, but only 13% of the natural products.
Looking at specificity, it appears that the commercial compounds were more likely, when they hit, to hit six or more different proteins in the set, and the natural products the least. Looking at it in terms of compounds that hit only one or two targets gave a similar distribution - in each case, the DOS compounds were intermediate, and that turns out to be a theme of the whole paper. They analyzed the three compound collections for structural features, specifically their stereochemical complexity (chiral carbons as a per cent of all carbons) and shape complexity (sp3 carbons as a percent of the whole). And that showed that the commercial set was biased towards the flat, achiral side of things, while the natural products were the other way around, tilted toward the complex, multiple-chiral-center end. The DOS-centric screening set was right in the middle.
The take-home, then, is similar to the other papers mentioned above: small molecule collections are inadequate, natural product collections are inadequate: therefore, you need diversity-oriented synthesis compounds, which are just right. I'll let Schreiber sum up his own case:
. . .Both protein-binding frequencies and selectivities are increased among compounds having: (i) increased content of sp3-hybridized atoms relative to commercial compounds, and (ii) intermediate frequency of stereogenic elements relative to commercial (low frequency) and natural (high frequency) compounds. Encouragingly, these favorable structural features are increasingly accessible using modern advances in the methods of organic synthesis and commonly targeted by academic organic chemists as judged by the compounds used in this study that were contributed by members of this community. On the other hand, these features are notably deficient in members of compound collections currently widely used in probe- and drug-discovery efforts.
But something struck me while reading all this. The two metrics used to characterize these compound collections are fine, but they're also two that would be expected to distinguish them thoroughly - after all, natural products do indeed have a lot of chiral carbons, and run-of-the-mill commercial screening sets do indeed have a lot of aryl rings in them. There were several other properties that weren't mentioned at all, so I downloaded the compound set from the paper's supporting information and ran it through some in-house software that we use to break down such things.
I can't imagine, for example, evaluating a compound collection without taking a look at the molecular weights. Here's that graph - the X axis is the compound number, Y-axis is weight in Daltons:
The three different collections show up very well this way, too. The commercial compounds (almost every one under 500 MW) are on the left. Then you have that break of natural products in the middle, with some real whoppers. And after that, you have the various DOS libraries, which were apparently entered in batches, which makes things convenient.
Notice, for example that block of them standing up around 15,000 - that turns out to be the compounds from this 2004 Schreiber paper, which are a bunch of gigantic spirooxindole derivatives. In this paper, they found that this particular set was an outlier in the academic collection, with a lot more binding promiscuity than the rest of the set (and they went so far as to analyze the set with and without it included). The earlier paper, though, makes the case for these compounds as new probes of cellular pathways, but if they hit across so many proteins at the same time, you have to wonder how such assays can be interpreted. The experiments behind these two papers seem to have been run in the wrong order.
Note, also, that the commercial set includes a lot of small compounds, even many below 250 MW. This is down in the fragment screening range, for sure, and the whole point of looking at compounds of that molecular weight is that you'll always find something that binds to some degree. Downgrading the commercial set for promiscuous binding when you set the cutoffs that low isn't a fair complaint, especially when you consider that the DOS compounds have a much lower proportion of compounds in that range. Run a commercial/natural product/DOS comparison controlled for molecular weight, and we can talk.
I also can't imagine looking over a collection and not checking logP, but that's not in the paper, either. But here you are:
In this case, the natural products (around compound ID 7500) are much less obvious, but you can certainly see the different chemical classes standing out in the DOS set. Note, though, that those compounds explore high-logP regions that the other sets don't really touch.
How about polar surface area? Now the natural products really show their true character - looking over the structures, that's because there are an awful lot of polysaccharide-containing things in there, which will run your PSA up faster than anything:
And again, you can see the different libraries in the DOS set very clearly.
So there are a lot of other ways to distinguish these compounds, ways that (to be frank) are probably much more relevant to their biological activity. Just the molecular-weight one is a deal-breaker for me, I'm afraid. And that's before I start looking at the structures in the three collections at all. Now, that's another story.
I have to say, from my own biased viewpoint, I wouldn't pay money for any of the three collections. The natural product one, as mentioned, goes too high in molecular weight and is too polar for my tastes. I'd consider it for antibiotic drug discovery, but with gritted teeth. The commercial set can't make up its mind if it's a fragment collection or not. There are a bunch of compounds that are too small even for my tastes in fragments - 4-methylpyridine, for example. And there are a lot of ugly functional groups: imines of beta-napthylamine, which should not even get near the front door (unstable fluorescent compounds that break down to a known carcinogen? Return to sender). There are hydroxylamines, peroxides, thioureas, all kinds of things that I would just rather not spend my time on.
And what of the DOS collection? Well, to be fair, not all of it is DOS - there are a few compounds in there that I can't figure out, like isoquinoline, which you can buy from the catalog. But the great majority are indeed diversity-oriented, and (to my mind), diversity-oriented to a fault. The spirooxindole library is probably the worst - you should see the number of aryl rings decorating some of those things; it's like a fever dream - but they're not the only offenders in the "Let's just hang as many big things as we can off this sucker" category. Now, there are some interesting and reasonable DOS compounds in there, too, but there are also more endoperoxides and such. (And yes, I know that there are drug structures with endoperoxides in them, but damned few of them, and art is long while life is short). So no, I wouldn't have bought this set for screening, either; I'd have cherry-picked about 15 or 20% of it.
Summary of this long-winded post? I hate to say it, but I think this paper has its thumb on the scale. I'm just around the corner from the Broad Institute, though, so maybe a rock will come through my window this afternoon. . .
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Natural Products
August 26, 2010
The Vinca alkaloids are some of the most famous chemotherapy drugs around - vincristine and vinblastine, the two most widely used, are probably shown in every single introduction to natural products chemistry that's been written in the past fifty years. But making them synthetically is a bear, and extracting them from the plant is a low-yielding pain.
A new paper in PNAS shows that there's still a lot that we don't know about these compounds. What has been known for a long time is that they're derived from two precursor alkaloids, vindoline and catharanthine. This new work shows that the plants deliberately keep those two compounds separated from each other, which helps account for the low yield of the final compounds.
As it turns out, if you dip the leaves in chloroform, which dissolves the waxy coating from the surface, you find that basically all the catharanthine is found there. At the same time, even soaking the leaves in chloroform for as long as an hour hardly extracts any vindoline - it's sequestered away inside the cells of the leaves. The enzymes responsible for biosynthesis are probably also in different locations (or cell types), and there are unknown transport mechanisms involved as well. This is the first time anyone's found such a secreted alkaloid mechanism.
Why does Vinca go to all the trouble? For one thing, catharanthine is a defense against insect pests, and it also seems to inhibit attack by fungal spores. And what the vindoline is doing, I'm not sure - but the plant probably has a good reason to keep it away from the cantharanthine, because producing too much vincristine, vinblastine, etc. would probably kill off its dividing cells, the same way it works in chemotherapy.
The authors suggest that people should start looking around to see if other plants have similar secretion mechanisms. And this makes me wonder if this could be a way to harvest natural products - do the plants survive after having their leaves dipped in solvent? If they do, do they then re-secrete more natural waxes to catch up? I'm imagining a line of plants, growing in pots on some sort of conveyor line, flipping upside down for a quick wash-and-shake through a trough of chloroform, and heading back into the greenhouse. . .but then, I have a vivid imagination. . .
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