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

Derek Lowe The 2002 Model

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

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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August 26, 2010

Vinca Alkaloids, And Where They End Up

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Posted by Derek

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. . .

Comments (9) + TrackBacks (0) | Category: Biological News | Natural Products


1. Anonymous on August 26, 2010 1:09 PM writes...

I am sure you meant yielding not yeilding :).

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2. barry on August 26, 2010 2:20 PM writes...

so now we've found binary weapons in plants, forming the toxin only when the leaf has been ingested and the compartmentalization is broken. That should work to deter any browser that shows learning behavior--but how do you stop a cow?

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3. Wave 124 on August 26, 2010 4:49 PM writes...

We put in a garden plant with vinca in the name - lost the tags but it might be Catharanthus roseus (Madagascar Periwinkle)- see Wiki Catharanthus article for pictures. The good thing is that deer and rabbits seem to avoid them so maybe they are protected by the same compounds. But the isolation woud still be a problem.

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4. Smarry on August 26, 2010 6:02 PM writes...

FYI there's a . instead of a > on the closing </i> tag for "Vinca", which is hiding the bit about chemotherapy and making the rest of the entry show up in italics.

Huzzah anyway for writing HTML by hand - too few people do that these days.

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5. drug_hunter on August 26, 2010 10:01 PM writes...

For years I've hoped to see a revival of natural products chemistry within Pharma but so far it isn't happening. A post like this is important because it highlights how the deeper our understanding of the subtleties of plant structures, the more we can learn about how to identify and extract novel compounds. Yes, of course, natural products chemistry is hard, compound ID is a bear, you can't synthesize analogs easily, etc etc. But the sheer chemical diversity still dwarfs anything we can do in the lab - nature puts DOS to shame. So for the especially challenging targets we'd love to tackle ("undruggable" targets, anyone?) natural products can be a hugely valuable resource if we allow ourselves to pursue that approach.

Anyone care to speculate on why pharma isn't doing more of this?

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6. boom on August 27, 2010 1:04 AM writes...

slightly off-topic, but that's a "Thing I won't work with right there"

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7. Jose on August 27, 2010 4:17 AM writes...

Drug_hunter: the NIH screening program had hits on some obscene number of plant extracts over 40 years, (50,000?) and two? three? went anywhere-taxol, the cardiac glycosides? and maybe Et 743/Yasmin.... that development rate makes "normal" pharma look like a hall-of-famer.

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8. drug_hunter on August 27, 2010 5:14 AM writes...

Jose: I completely agree with you that the "old-fashioned" way of looking for hits from natural products was extremely inefficient. That's why I'm looking for improvements -- as I said in my post, "the deeper our understanding of the subtleties of plant structures, the more we can learn about how to identify and extract novel compounds." We need access to these strange & wonderful compounds in order to tackle the very hard targets we will need to go after in the future. Life is not just about ATP-directed kinase inhibitors, PDEs, etc.

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9. David Kroll on August 29, 2010 9:15 PM writes...

Derek, what a fascinating paper! Sorry that I missed this post until tonight. This is going right into my next natural products lecture.

Jose, I'm not sure if you're only referring to the NCI screening program or plants only but there have been far more drugs than that. However, many are semi-synthetic derivatives made necessary by the poor solubility of the natural products at concentrations at which we need them plus poor human bioavailability.

Derek's post points to a major problem, particularly with plants: supply issues. We are spending much more time today with collaborators employing sources that can be cultured, such as the filamentous fungi collection of Cedric Pearce at Mycosynthetix.

I tend to be on of the mind of drug_hunter regarding the wonder at the chemical diversity of nature. And while the natural products themselves might not be drugs, very simple chemical modifications can be made such as in the case of the epothilone, ixabepilone, or the camptothecin, topotecan.

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