I like this review, but I’ve seen it before. Well, not this exact manuscript, but every few years it seems there’s another one with a similar title, something about “Incorporating Silicon Into Drug Structures”. I am guilty of the exact same thing, though: here’s a blog post from 2004 on the topic, and here’s one from 2012.
This latest paper incorporates some recent references, but looking through it, I think it’s fair to say that we don’t know that much more about organosilanes as drugs than we did in 2012. At right is the paper’s comprehensive list of all the organosilanes that have entered human clinical trials, and unless I’m missing something, none of them are particularly recent. There have been papers with in vitro studies since then, or animal work, but I believe that the most recent clinical work reported has been the photodynamic phthalocyanine PC-4, which was published in 2010. If anyone knows of any Si-containing drug candidates that are currently in the clinic, I’ll be glad to correct that impression.
So why is this? The obvious answers, which I think in this case are also the correct ones, is that no one has yet identified a particular property that silicon substitution brings to a drug structure that is in much demand, and that any such properties (which are likely case-by-case things) have so far been deemed not worth the trouble or risk involved. Silicon is most certainly not carbon, and philosophically, you’d imagine that having a not-quite-carbon atom to mess around with might be the source of a lot of interesting structures and biological activity. But so far, that hasn’t quite been the case. It’s probably true that a larger or more concerted effort might well uncover some more interesting things, but who’s going to make such an effort? “This could be interesting, we’re not sure” is not quite enough of a rationale for the kinds of money and time that go into drug research. And some would look at the record so far and say “This could be interesting, but probably not”, even thought that might be unfair.
That’s not to say that silicon can’t someday bring something to the party. You’ll note from that graphic that most of the substitutions have been pretty straightforward trimethylsilane-for-tertiary-butyl sorts of things (the only organosilane I’ve ever synthesized on a drug project was exactly that, and boy, did I get the fish-eye for making it). There are surely a lot of silicon-containing heterocycles, for example, that we either don’t know how to synthesize yet, or have not really been evaluated in drug structures. One of these might be just what some project is looking for.
But as long as it’s in the “might be” category, the chances that someone will go to the trouble of finding that out are relatively small, compared to the option of sticking with the more common elements and just making more analogs. If there were more commercially available intermediates and building blocks of this type, chances would go up – but in order for someone to figure out how to make them and then offer them for sale, it would help if there were more interest among the customers. Chickens and eggs, once again. . .