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Terra Incognita

I was thinking the other day about the sheer number of reasonable chemical structures that have never been made. Chemical space is famously roomy – that’s how we make a living in the drug industry, since we prefer to make things that have never been made before. And it still surprises non-chemists when I tell them that I make new compounds all the time – the feeling, I think, is that anything that’s reasonably easy to make surely must have been mined out long ago. Not so. (It’s worth remembering, though, that just because something’s never been reported doesn’t always mean that you can’t buy it).
What brought this to mind was a steroid structure that I saw during a presentation. Looking at it like a medicinal chemist, I wondered idly if the carbons in the famous steroid backbone had ever been swapped out much with oxygen or nitrogen atoms. And in a few cases they have (more for oxygen, in some natural products), but for the most part, no. You can drop a tertiary amine into some spots on the steroid framework and immediately come up with no literature hits whatsoever. Many others yield only a handful.
It’s worth noting that the partially-aromatized steroids have had some of this kind of work done on them – for example here and here. The aromatic rings give you a bit more of a handle to work with, but even here it’s not like the literature is always packed with examples.
So there’s as bioactive a scaffold as you could ask for, but many of the simple analogs still haven’t been described. To be fair, these azasteroids aren’t simple to make, and probably wouldn’t have steroid-like activities in many cases. (Their natural receptors sure aren’t expecting a basic amine in those spots). But many azasteroids do show biological activities, and I’d be quite surprised if these unknown compounds were pharmacologically inert. It’s just that there’s been no particular reason to make any of them yet. Chemical space is so huge, and our ability to explore it has been with us for such a relatively short time, that we just haven’t gotten around to them yet.

8 comments on “Terra Incognita”

  1. Anonymous says:

    Just about germane: years ago Dasent wrote a lovely book “Nonexistent compounds”. It’s a good way to learn some chemistry.

  2. NJBiologist says:

    Y’know, steroids like that might make interesting tools for separating actions at traditional (DNA-binding) and non-traditional (GPCR/unknown) steroid receptors.

  3. JasonP says:

    Well, you THINK you make new chemical species every day, but there is no telling what labs have made and are hiding across the world. 🙂

  4. Jose says:

    Some of those amino-steroids might be in the running for the “Pole of Synthetic Inaccessibility” prize, I think.

  5. chemist says:

    Caveat emptor: if you are relying on SciFinder to determine whether or not a structure (or reaction) is known you could be deluding yourself and others. I have held papers in my hand, drawn the structures and SciFinder does not find the compounds or source documents.
    (You can sometimes have better success using CASOnLine.)

  6. MoD says:

    Interesting post Derek. Way back (~18 yrs ago – OH MY!) when I was an undergraduate, I was making 16-azasteroids. Why? Because we had some nice methodology that allowed us to. Very interesting molecules, including aromatic pyrrole D-rings. My advisor had some connections, so we ended up sending them to the NCI or NIH for their screening collection. We never wrote a publication so you will not find them using any searches.

  7. Cartesian says:

    May be with a new model for atom it will be better in order to discover some new things.
    See article 3 part one and two here :

  8. KY says:

    i believe that Gribble at Dartmouth had been funded to do exactly that a few years ago and came up with CDDO, the analogues which i had to synthesize.

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