4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki-Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies.
Fiche publication
Date publication
janvier 2016
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Pr SAPI Janos, Dr COCHARD Marie
Tous les auteurs :
Cornelio B, Laronze-Cochard M, Ceruso M, Ferraroni M, Rance GA, Carta F, Khlobystov AN, Fontana A, Supuran CT, Sapi J
Lien Pubmed
Résumé
Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para-position were prepared by palladium nanoparticle-catalyzed Suzuki-Miyaura cross-coupling reactions and evaluated as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl-aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides.
Mots clés
Carbonic Anhydrase Inhibitors, chemical synthesis, Catalysis, Crystallography, X-Ray, Drug Design, Humans, Isoenzymes, antagonists & inhibitors, Models, Molecular, Nanostructures, Neoplasms, enzymology, Palladium, chemistry, Structure-Activity Relationship, Substrate Specificity, Sulfonamides, chemical synthesis
Référence
J. Med. Chem.. 2016 Jan;59(2):721-32