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One For the Brave

B-N structureI was interested to see a recent paper in Organic Letters on a class of compounds I’d never seen before: 1,2-dihydro-1,2-azaborines. There’s the structure, in case that doesn’t immediately call something to mind.
These things, which are isoelectronic with benzene, were made by the Liu group at Oregon. Their method (ring-closing metathesis) for making them seems superior to the rather sparse techniques that have been available up until now, and they’ve prepared a number of useful and interesting intermediates. They’re rather stable – even the B-H compound with an N-ethyl group, the simplest in the paper, can be run down a silica gel column. An X-ray structure shows that the ring is indeed flat, and it seems to be aromatic and delocalized.
So. . .what I’d like to know is, who’s going to be the first person wild-eyed enough to put this in a drug candidate structure? Boron has a bad reputation (“boron for morons”, as they say), but hey, Millennium is out there making money with Velcade, a boronic acid. I have absolutely no idea what the fate of this heterocycle is in vivo, what its toxicity might be or what it gets metabolized to (if anything). And neither do you, nor does anyone. Let’s find out!

11 comments on “One For the Brave”

  1. DLIB says:

    Here’s one that might be interested:
    GlaxoSmithKline and Anacor Pharmaceuticals form alliance to develop systemic antivirals and antibiotics based on boron chemistry

  2. SBC123 says:

    Interesting compound. Assume the thing is aromatic, then the Boron might not be that electrophilic and therefore not that toxic in vivo. If the compound does not fall apart easily in the body, it would be a very interesting isostere for benzene.

  3. milkshake says:

    There was lots of simple organoboron-amine complex kind of compounds, with anti-glycemic properties. None ever made it through clinic.
    To replace benzene with something bizzare, I would rather use carboranes – these have a nice simple chemistry (if you buy starting carborane), behave like greasy aromatic system and are rock stable – and they were tested in clinic, for neutron-capture radiotherapy. Not that carboranes are exactly isosteric – but nowadays people are putting worse stuff in their molecules (adamantane or Ar-SF5 group, for example)

  4. psi*psi says:

    Noo! Why would you want to waste something beautiful and flat like that in a drug! Fuse a few of them together and see what it does in a transistor!
    (no, I’m not biased 😉 )

  5. WonderDrug says:

    Fear not! There’s enough boron for all of us kid 🙂

  6. processchemist says:

    two boronic acids, ABBA and BoroGLU (names used by biologists) show potential good properties against drug resistance in oncologic patients…

  7. Anonymous says:

    Please enligthen a non-chemist: WHY is boron for morons? Why do you guys shy away to use Boron for your compounds?

  8. bootsy says:

    From ignorance comes fear. Still, I think the first person to put one of these in a analog and register it better be prepared from some ribbing at the least. I wonder what the in silico prediction tools will do with this.
    While we’re at it, we tend to shy away from silicon too. Though I remember someone in a past life submitting a few silanes for assay.
    If these turn out to be well tolerated, and a good replacement for a phenyl ring, there are a lot of patents to be busted. (Excuse me while I go write up a business plan.)

  9. eman says:

    If it is sufficiently like a benzene ring compound, then the receptor molecules may simply see it as benzene compound.

  10. DrSnowboard says:

    Well, silicon switch was the raison d’etre for amedis, who were acquired by paradigm , which was obviously the technology that takeda were after when they swallowed paradigm…
    Boron switch anyone?

  11. Jose says:

    Along the same lines, on the back pg of the 11/4 NY Times Education section, there is an add for CUNY. A side blurb says, “The Malaria Combat Team: [snip] Dr. Sanchez-Delgado and doctoral student Chandima Rajapakse insert the metal ruthenium into chloroquine to make it invisible- and therefore lethal- to the parasites. This modified drug also promises to fight cancer. Lab tests are starting in both areas.”
    I don’t want to denigrate their research, but….oncology, maybe, but the tox is going to be a non-starter for malaria!

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