This is a slightly provocative post – I would welcome comments.
When the Nobel prizes were announced this year there was consternation in some of the chemical blogosphere that the chemistry prize had gone to a biologist (see links in my earlier post). But others argued that chemists had lost the plot and that biology is now where the action is. It was important not just to do research in one’s own community but to appeal to a wider audience.
A lot of chemistry (reflected by the chemical blogosphere) is concerned with making compounds. A subset of this is the synthesis of natural products, compounds produced by organisms (fungi, bacteria, plants, marine invertebrates, etc.). These compounds often have biological activities (e.g. to kill other other organisms) and are frequently useful in medicine. Typical examples are taxol (anticancer, from the Pacific yew tree) , ciclosporin (immunosuppressant from a fungus) and vancomycin (antibacterial from bacteria). They are in widespread clinical use and this is reflected by a very large literature. I have used Pubmed to get a base metric – I simply enter the name and see how many references there are and the earliest date:
- taxol (1971) 12505 references
- vancomycin (1955) 12225 references
- ciclosporin (1980) 20505 references
(The numbers are approximate as names can vary – we also find “cyclosporin” – but Pubmed with its MeSH terminology is very good about synonyms).
These compounds are difficult and expensive to extract from natural sources so there is clear value in trying to make them more cheaply by synthetic chemistry. Moreover it may be possible to synthesize similar compounds which are better or much easier to make or both. So not surprisingly the pharmaceutical industry (in which I have worked) and academia are interested in synthesizing complex molecules. And this is reflected, for example, in TotallySynthetic‘s excellent blog where he reviews the syntheses of natural products.
But are the targets chosen because they are useful, or because they are difficult? And do the results of such synthesis find their way into the clinic or use as biological tools? To be fair, it’s important to remember that it takes a long time to develop drugs, and also that chemical synthesis might be a prerequisite step before any other science can be done. Bearing that in mind, here are the Pubchem metrics for the compounds in the last 2 months of Totally Synthetic’s blog (back to 2006-09-01). The table shows:
- the name used in the blog. (Sometimes there are additional letters which I have removed to increase the hits). Bear in mind that some compounds might have synonyms, but Pubmed is pretty good about this.
- The date of the first abstract in Pubmed. This is often the first report of the isolation of the compound and its possible biological activity.
- The number of papers in chemistry journals. These are mostly reporting the synthesis, but some might discuss the elucidation of structure. The latest chemistry paper as abstracted by Totally Synthetic is sometimes not yet included in Pubmed, but in general all the major chemistry journals are reviewed.
- The number of papers in “non-chemistry” journals. This is subjective but these are the ones where biosynthesis, biological activity, medicinal properties, etc. are likely to be reported.
| name | earliest data | chemistry pubs | non-chemistry pubs |
|---|---|---|---|
| Acutiphycin | 1999 | 1 | 0 |
| Latrunculin | 1983 | ? | 757 |
| Monocerin | 1970 | 2 | 0 |
| Apoptolidinone | 2001 | 4 | 0 |
| Strychnofoline | 2002 | 2 | 0 |
| Manassantin | 1987 | 0 | 14 |
| Mitorubrin | 1965 | 3 | 3 |
| RK-397 | 1993 | 3 | 2 |
| Clavilactone | 2000 | 1 | 1 |
| Chartelline | 2005 | 3 | 0 |
| Antheliolide | 2005 | 1 | 0 |
| Sylvaticin | 1990 | 2 | 4 |
| Elatenyne | 2006 | 1 | 0 |
| Platensimycin | 2005 | 2 | 5 |
| guanacastepene (sic) | 2000 | 22 | 1 |
| Bengazole | 1993 | 4 | 3 |
| Batzelladine | 1999 | 19 | 3 |
| Marinomycin | 2006 | 0 | 1 |
| Hexacyclinol | 2002 | 3 | 2 |
| Himgaline | 2006 | 1 | 0 |
| Polygalolide | 2003 | 0 | 1 |
| Leucascandrolide | 2000 | 15 | 0 |
Out of 22 compounds a few have a significant biological literature. Many, even when reported some time back have none. So it is difficult to argue that they are synthesised because they are interesting.
There are other reasons than interesting biology for doing this type of synthetic chemistry. It can lead to new synthetic methodology which could be of use to the chemical industry in general. And it may be good training for the chemistry-specific part of a PhD. So I welcome comments – they will all be posted.
Is natural product synthesis interesting? To me, hell no! I don’t get it. At all. Not one bit. That being said, I understand the push for better routes to biologically active molecules such as paclitaxel. What I fail to grasp is why some random compound, extracted from an esoteric sea sponge is more likely to yield cancer curing compounds than your average organic chemist run amok in the lab.
I do understand that the methodologies developed by these research groups, the new uses for old catalysts, or the new functional group transformations are extremely useful to the rest of us chemists. I agree with your point that total synthesis is a great training for a synthetic chemist. I just wish the choice of synthesis target was for more medicinally useful reasons.
(2) Thanks very much Propter. There are ideas here I may developed in later posts. But let’s see who else posts…
I guess you’re not surprised I’m interested in this post. Yep, some natural product synthesis is done “for the sake of it” – but the funding keeps rolling in from Big Pharma – why? Because it trains damn good chemists at the end of the day. Sure, the type of targets inhabiting the NP part of chemical space are generally different to those in the Candidate Drug section, but the skills used to make them are still very similar.
The best syntheses showcase new methodology to make an interesting target. But it the target is new, it’s hardly surprising there isn’t a lot of biological data around. It takes time to generate useful results from the 1 mg of synthetic product!
My natural product isn’t the most exciting (but it is seriously biologically active), but I’ve learnt soooo much in the process, and hopefully it will show that our methodology is useful. I’m planning to work on another for my post-doc, and I’m focusing my ideas towards antibiotics. My reasons are transparent enough.
I agree that some natural product are done for the sake of it. But this is during this process that you could develop new methodologies that could later be usefull to really biologicaly active compounds. Develop a synthetic route to a moderately active compound could also give you analogs (potentialy much more active) that were not accessible from the natural product. I think that total synthesis is an extraordinary stimulation to discover new reactions: each natural product could have a particulary synthetic problem that requires a new process to be discover. Total synthesis of random but complexe natural products by new methods is part of the fundamental research (what is the real interest to land on the moon or mars?).
Pharma companies are more and more interested by complexe natural products and are ready to make those kind of compound via synthetic process that require more than 20 steps: halichlondrin analog or ecteinascidin 743;
I am a huge fan of total synthesis even it is a real pain in the … when you need to scall up more than 25 steps but when you finally get 1 or 2 mg of the final compound, it is so good………..
Propter doc when you said “Is natural product synthesis interesting? To me, hell no! I don’t get it. At all. Not one bit.” why do you then reconize that “I do understand that the methodologies developed by these research groups, the new uses for old catalysts, or the new functional group transformations are extremely useful to the rest of us chemists.” extremely usefull are your words, I think that you just don’t like total synthesis but you recognize its interest.
(3), (4) Many thanks for posting. I’ll reply briefly and hope that more people post (one of the reasons for raising the subject). I’m also genuinely ignorant of whether there is biological benefit in natural product synthesis and I’d welcome real cases. I also agree that in some cases it is too early to say whether something is going to be interesting – although the table shows that there are a lot of targets that were discovered a long time ago and there has been no biological work. Of course they may have been waiting 20 years for someone to synthesize enough to do some work with. However biological methods are increasingly sensitive and I doubt this is the reason. I also question whether this is actually the training that the pharma industry most needs and I’ll post about that later.
Please keep posting – I’d like to be able to summarise this objectively from your contributions.
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Is Natural Product Synthesis Interesting?
Absolutely! (In no particular order)
1) It trains synthetic chemists for the pharmaceutical industry
2) It drives the development of innovative new reactions.
3) It enables access to amounts of material suitable for biological screening (not always possible from natural sources)
4) It enables access to derivatives and analogs which may be more potent or more suitable as drug candidates (see Danishefsky’s recent Perspective in JOC, 2006, 8329-8351)
5) Sometimes it can just be so damn elegant or clever or efficient that it is no less interesting than a Mozart Symphony, a Dali painting, or a Jordan slam dunk – which is to say maybe it doesn’t always need to save lives to be of value.
Cheers,
Russ
(7) Thanks! Well argued points.
Please keep posting – it will be useful to know whether the arguments presented are generally accepted.