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Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms
journal contribution
posted on 2020-03-09, 11:41 authored by Francesca Mancuso, Anna Di Fiore, Laura De Luca, Andrea Angeli, Simona M. Monti, Giuseppina De Simone, Claudiu T. Supuran, Rosaria GittoWe report the synthesis
and biochemical evaluation of a series
of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides
(5a–s) 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.