Quite a while ago (sheesh, five years - this is an old blog, as these things go!), I wrote about a "Chemical Wish List". There are a lot of elements and functional groups that nature has not provided us with, and we could really use them. The earlier post was a request for something the size of fluorine that's electron-donating instead of electron-withdrawing, but today I have another one for the list.

I want a nitro group, or something a lot like it, that's metabolically stable. Nitro's an odd duck, as the structure in its brief Wikipedia entry will show. That drawing is a compromise attempt to represent reality (dotted lines in chemical structures are a giveaway for that). You can draw other resonance structures, all of which approach the truth to greater or (mostly) lesser degrees. Basically, the two oxygens have more electon density on them that usual, and the nitrogen has less. Neither oxygen has a full negative charge on it, but they're closer to it than usual.

And that's what makes nitro interesting. It's quite a polar functional group, and compounds that contain it reflect that. Take a look at the simplest organonitro compound, nitromethane. It dissolves freely in water, and boils at nearly the same temperature, 100 degrees C. Boiling point is a fairly good surrogate for polarity, other things being equal, since it's measuring how well the molecules prefer each other's company in the liquid state, as opposed to flying off on their own in the gas phase. For comparison, methanol (CH3OH) boils at about 65 degrees C, and methylamine is wimpy indeed, fizzing away at about minus 6. Now, there are some molecular weight differences in there which can't be totally ignored, but there's no doubt that nitro is one polar group.

We need polar groups in medicinal chemistry. Those, along with the general shape of the molecule, are the biggest parts of binding energies to our in vivo protein targets. Nitro groups uniquely offer a positive charge right next to a forked arrangement of partial negatives, and I'm sure we could do a lot with that - if the darn things didn't get chewed up in living systems. That nitrogen is nearly as oxidized as it can get (well, there's nitrate anion, true), and there are plenty of systems in the body ready to bring it back down.

That's where the trouble starts. If you go all the way down from nitro, you end up with an amine (NH2). But the intermediates along the way - hydroxylamines, nitrosos, all that kind of thing - are rather reactive and nasty. Those are what give nitro groups their bad reputation in medicinal chemistry - too many of them, especially the ones where the nitro is on an aromatic ring, are experimental (or, gulp, real-world) carcinogens because of those metabolites. The same thing happens to aryl amines, too, because other enzyme systems can oxidize them up to the nasty middle steps. I don't think that they make it all the way up to nitro in vivo, but more perverse things than that happen in biochemistry all the time. For those who don't know this stuff and would like to know more, here's a nice presentation on the basics of drug metabolism - navigate down to #88 in the frame to get to the nitro section.

Now, it's not like there are no nitro-containing drugs. Putting the group on a five-membered heterocyclic ring is often a tolerable move, and there are plenty of examples of that working out. But there's always going to be some suspicion attached to the group, and you're never sure that things are going to work out, since human metabolism can differ from your animal models. Most medicinal chemists opt for caution, and don't put nitro groups on any of their aromatic rings to avoid heartbreak later on. (And of course, there are aliphatic nitros, but those have their own problems).

No, what I want is something that's the size, shape, and polarity of a nitro group, but is rock-solid to metabolism. Sort of a trifluoromethyl group with lots of charge on it. We could certainly have a good time with one of those. . .