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Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms

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posted on 09.03.2020, 11:41 by Francesca Mancuso, Anna Di Fiore, Laura De Luca, Andrea Angeli, Simona M. Monti, Giuseppina De Simone, Claudiu T. Supuran, Rosaria Gitto
We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)­benzene­sulfonamides (5as) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeutics. X-ray crystallography confirmed that this class of benzenesulfonamides binds CAs through the canonical anchoring of the benzene­sulfonamide moiety to the metal ion and a tail-mediated recognition of the middle/top area of the active site cavity. Compound 5e (R = 2-Cl) demonstrated relevant selectivity toward brain-expressed hCA VII. The best balancing in binding affinity and selectivity toward tumor-expressed hCA IX/hCA XII over ubiquitous hCA I/hCA II was found for inhibitor 5o (R = 3-NO2). Notably 5b (R = 2-F) proved to be the most efficacious inhibitor of hCA XII for which computational studies elucidated the CA recognition process.

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