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Medicinal Chemistry

Chemists bring substituted bicyclopentanes into reach

Synthetic route developed by Scripps and Pfizer could widen access to arene analogs

by Leigh Krietsch Boerner
November 9, 2020

 

20201109lnp3-scheme.jpg

Flat is generally out of favor with medicinal chemists. For several years, drug hunters have been leaning away from substituted planar arenes and toward more architecturally complex compounds, which often have better solubility, permeability and stability and sometimes better bioactivity. Now Phil Baran, Michael Collins, and coworkers at Scripps Research and Pfizer have developed a new synthetic route for a class of non-planar molecules on medicinal chemists’ wish list, but were previously hard to access in high yields (ChemRxiv 2020, DOI: 10.26434/chemrxiv.13120283.v1). The work has yet to undergo peer review.

Chemists have long known that 1,3-difunctionalized bicyclopentanes can act as bioisosteres, compounds that have different structures but similar drug properties, for para-substituted arenes. Researchers have suspected that ortho- and meta-substituted bicyclopentanes could also act as bioisosteres but lacked the data to support their theory. That’s because they’re more challenging to make in large quantities—in fact, Baran’s group tried several different strategies before landing on one that worked. The successful synthesis involves first making a bicyclopentane precursor, then using that compound to make several different kinds of ortho- and meta-substituted benzene analogues (shown).

The team is in the process of testing the compounds through both biological and computational studies to see if they are suitable bioisosteres. If they are, the bicyclopentanes might get around limitations of the substituted arene rings, which can be metabolized into potentially toxic compounds.

These difunctionalized bicyclopentanes have a similar 3-D shape as the arene, but the body can’t metabolize them in the same problematic way as the arene, Baran says. “Now you have the same orientation in an enzyme pocket, but without the problem of the liver chewing it up and turning into something toxic.”

This is one of the few—and one of the strongest—examples of syntheses that allows scientists to mimic the meta- and ortho- isomers, says Daniele Leonori, an organic chemist at the University of Manchester. Medicinal chemists in industry will be very excited about this development, he says.

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