title: Development of potent carbonic anhydrase inhibitors incorporating both sulfonamide and sulfamide groups.
abstract: A series of compounds incorporating both sulfonamide and sulfamide as zinc-binding groups (ZBGs) are reported as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Crystallographic studies on the complex of hCA II with the lead compound of this series, namely, 4-sulfamido-benzenesulfonamide, revealed the binding of two molecules in the enzyme active site cavity, the first one canonically coordinated to the zinc ion by means of the sulfonamide group and the second one located at the entrance of the cavity. This observation led to the design of elongated molecules incorporating these two ZBGs, separated by a linker of proper length, to allow the simultaneous binding to these different sites. The "long" inhibitors indeed showed around 10 times better enzyme inhibitory properties as compared to the shorter molecules against four physiologically relevant human (h) isoforms, hCA I, II, IX, and XII.
authors: Istituto di Biostrutture e Bioimmagini-CNR , via Mezzocannone 16, 80134 Napoli, Italy.
authors: Katia
authors: K
authors: D'Ambrosio
authors: Fatma-Zhora
authors: FZ
authors: Smaine
authors: Fabrizio
authors: F
authors: Carta
authors: Giuseppina
authors: G
authors: De Simone
authors: Jean-Yves
authors: JY
authors: Winum
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D007527:Isoenzymes; D013449:Sulfonamides; C576045:4-sulfamidobenzenesulfonamide; D000096926:Benzenesulfonamides