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Drug Industry History

C-Nucleosides Never Went Away

Here’s a paper in J. Med. Chem. calling for a revival of work in the C-nucleoside area. To some extent, these compounds never went away, but it’s certainly true that there was a period where many more groups were working on them. When I was looking for an undergraduate research project to do during my senior year at Hendrix, back in 1982-83, I chose to work on C-nucleosides, because I’d seen so much about them. (I made a few, slow and inefficiently). My impression is that from the mid-1970s until well on into the 1980s, there was a lot more done in this area than there has been for the last twenty years. (Although not a C-nucleoside itself, the discovery of AZT as a therapy for HIV came as a result of all the altered nucleosides and nucleoside mimics that had been synthesized in the 1970s). There are an awful lot of variations that can be rung – carbocycles, azacycles or opened rings instead of sugars, various non-natural substituents on the carbohydrate-derived part in general, and every variety of heterocycle you can think of attached to these via the C-C linkage. I would not wish to guess how many such compounds have been made over the years.

Medicinal chemistry does tend to work in waves like this, though. As the 1990s went on, the possibilities of kinase inhibition became apparent, and by the time you get to the early 2000s there are kinase inhibitors all over the literature. The classic aminopyrimidine core got a real workout; I wouldn’t want to guess how many compounds of that class got described, either (and they’re still showing up). Then as other “hinge-binding” groups were explored, the field just kept going on and on. It’s a rare kinase indeed that hasn’t had some compound or group of compounds attached to it as potential inhibitors by now (not that every single one of those assignments is useful, or even accurate).

There are others. A big pile of literature from the 1980s (and before and after) describes all sorts of peptidomimetics, especially directed against elastase, renin, and a few other targets. There was a vast amount of work put into making short peptides into drugs, sometimes with success, but usually not. N-methylation, D-amino acids, peptoids, statines, retro-inverso peptides – the list goes on. And in the same period, the list of “warhead” groups to affect protease targets expanded as well, and the intersection of those modified peptides with (say) trifluoromethyl ketones is a mighty thick stack of papers and patents. If the lesson of the kinase boom was “Yeah, we can probably find an inhibitor for that enzyme”, the lesson of this era was “No, we don’t have any general recipe for turning an oligopeptide into a drug”.

Someone older than I am would probably talk about the times when there were antifolates everywhere or all the tricyclics as CNS agents. After a while, there’s a perception that such areas as pretty well mined out – the easier compounds have all been made, the better targets worked over, the patent space cluttered beyond repair. But as the C-nucleosides show, biology and disease don’t care as much about our med-chem fashions and perceptions. Active compounds are active compounds, whether we think their structures have been beaten to death or not.

One comment on “C-Nucleosides Never Went Away”

  1. Calvin says:

    I’ve just had that shudder go down my spine. I spent my PhD working on C-nucs. All I can say is that deoxyribose was a pain to work on. Stick to ribose or something else but the deoxy boy is a pain. I’m sure there are great compounds lurking in there but on the way there is going to be a great deal of swearing and shouting from the poor soul whose job it is to make some compounds. Given the huge success of the HCV nucs it wouldn’t surprise me if there were some real gems out there. Won’t be me that finds them. I’ve had enough nervous breakdowns over those things.

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