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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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November 7, 2012

Silicon In Drug Molecules: Not Quite There

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Posted by Derek

Now here's a subject that most medicinal chemists have thought of at one point or another: why don't I put a silicon into my compounds? Pretty much like carbon, at least when there's only one of them, right? I've done it myself - I was working on a series of compounds years ago that had a preferred t-butyl group coming off an aryl ring (not anyone's favorite, to be sure). So I made the trimethylsilyl variation, and it worked fine. We had some patent worries in that series, and I pointed out that a silicon would certainly take care of that little problem, but it was still a bit too "out there" for most people's comfort. (And to be fair, it didn't have any particular other advantages; if it had stood out more in activity, things might have been different).

I wrote a bit about this subject a few years ago here, and mentioned a company in the UK, Amedis, that was giving silicon-for-carbon a go. This idea did not, in the end, set much on fire. Amedis was bought by Paradigm Therapeutics in 2005, and a couple of years later, Paradigm was bought out by Takeda. I'm not sure if there's any remnant of the Amedis silicon era left in Takeda's innards by now; if there is, I haven't come across it.

There's a new paper on medicinally active silicon compounds, though, which might get people thinking about this whole idea once more. It's a roundup of what's known about the biological properties and behavior of these things, and will serve as a handy one-stop source for all the reported drug-like molecules in the class. As far as I can tell, the most advanced silane ever in humans has been Karenitecin, a camptothecin analogue that went into Phase III back in 2008 (and does not seem to have been heard from since).

All silicon needs is one success, and then people will take it more seriously. So far, the right combination of activity, interest, and need hasn't quite come together. If you're thinking of giving it a try, though, this new paper is the first place to start reading.

Comments (18) + TrackBacks (0) | Category: Odd Elements in Drugs


1. Chemjobber on November 7, 2012 10:08 AM writes...

How is Concert going in its D-for-H swapping?

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2. newnickname on November 7, 2012 10:15 AM writes...

I have pushed for silicon-containing targets on many occasions and, except in one case, was not allowed to pursue any of them. I'll have to check the J Med Chem Derek cites, but there were (still are?) no known mammalian enzymes that process Si. (Some plants and lower organisms process Si.) Except for a few classes (silatranes), tox (due to Si itself) is low.

I still have some easy to make Si-containing targets on the drawing board but they will likely never see the light of day.

Management tells us to think outside the box, come up with something new, push back the frontiers of drug space, dare to be different and then kill every idea that isn't a copy cat or me-too.

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3. John Wayne on November 7, 2012 10:33 AM writes...

I've done a C for Si swap in a handful of projects. The exchange is usually tolerated (and sometimes addresses issues), but it often comes with an increase in LogD that appears to lead to an unacceptable tox and off-target profile: CYP inhibition, stability in vivo, poor solubility, and some poor 2 week rat tox results.

I would look at a C to SI swap in projects wherein the leads are too polar (aka not often).

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4. A Nonny Mouse on November 7, 2012 11:08 AM writes...

I met William Bains (Amedis founder) a couple of years ago. Very "interesting" chap. Worth a Google.

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5. simpl on November 7, 2012 11:28 AM writes...

For the sake of completeness, silicones have long been on the market to combat flatulence. Dow Corning goes into some of the science here.

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6. Harold Urey on November 7, 2012 12:23 PM writes...

@chemjabber--interesting question, but can we stay on topic?

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7. petros on November 7, 2012 12:31 PM writes...

William Bains is indeed an interesting chap who's been involved in a number of things.

Amedis switched out of Si chemistry even before it went into Paradigm. But prior to that I saw two or three interesting talks on their work.

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8. yoyomama on November 7, 2012 2:15 PM writes...

There is a silicon containing triazole agricultural fungicide called Fusilazole as well as a pyrethroid type insecticide with the common name of Silafluofen. These were discovered back in the 1980's at DuPont and Hoechst respectively and have the silicon in what would normally be a carbon chain(not as a substitutent).

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9. David Young on November 7, 2012 2:55 PM writes...

I recall keeping track of the Silatecans about 10 years ago or so. Most of the work was done at the University of Kentucky. At that time I had lots of hopes that a "better irinotecan" would be found. There were a lot of research 10 years ago on analogues, Silicon based or not. But none of these panned out. The fact that research goes on may be more academic.

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10. Chemist on November 7, 2012 3:13 PM writes...

Silicon has been incorporated in an azole antifungal which is used in agriculture: flusilazole

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11. Matt B. on November 7, 2012 6:37 PM writes...

Para-chlorophenylsilatrane is a strong, fast acting convulsant was investigated as a rat poison. A quick googling suggests it may have also been investigated as a chemical weapon by the South Africans.

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12. Sisyphus on November 7, 2012 9:59 PM writes...

Dammit Jim, I'm a doctor not a bricklayer!

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13. David Bradley on November 8, 2012 3:05 AM writes...

I'd always assumed there was some bio reason no drug people used Si, I imagined sandy metabolites accumulating in the bladder or something...but it's just tradition not to use it?

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14. anonymous on November 8, 2012 4:21 AM writes...

replacing C by Si is an interesting strategy to block metabolism pathways via unsaturated intermediates

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15. themoleculargame on November 8, 2012 4:44 AM writes...

Having worked at Bionumerik Pharmaceuticals in the early 2000's, I can share that Karenitecin has saved a few lives. Small numbers, but probably quite significant for the cured patients. Make it or not to market, one could argue that this silicon-based drug has already brought some contribution to medicine. For the anecdote, the compound has been named after one of our administrative assistant that passed away from cancer.

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16. DrFreddy on November 8, 2012 2:48 PM writes...

I used to work for a company that loved attaching SF5-groups(!) to known series. It did virtually nothing in vivo, good or bad, but did wonders for IP.

Long gone are the glorious days of a cutting-edge scientific pharmaceutical industry.

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17. Scott Sieburth on November 8, 2012 2:59 PM writes...

In addition to Moberg's flusilazole (see above) there is one other organosilane produced for its biological activity, silafluofen - a pyrethroid insecticide.

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18. churl on November 8, 2012 6:48 PM writes...

No!!! The GM risk is too high!
(see forecast by Asimov

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