title: Carbonic anhydrase inhibitors: inhibition of the human isozymes I, II, VA, and IX with a library of substituted difluoromethanesulfonamides.
abstract: An inhibition study of the human cytosolic isozymes I, and II, the mitochondrial isoform VA, and the tumor-associated, transmembrane isozyme IX of carbonic anhydrase (CA, EC 4.2.1.1) with a library of aromatic/heteroaromatic/polycyclic difluoromethanesulfonamides is reported. Most of the inhibitors were derivatives of benzenedifluoromethanesulfonamide incorporating substituted-phenyl moieties, or were methylsulfonamide and difluoromethyl-sulfonamide derivatives of the sulfamates COUMATE and EMATE, respectively. Except for the methylsulfonamide-COUMATE derivative which behaved as a potent CA II inhibitor (K(I) of 32nM), these sulfonamides were moderate inhibitors of all isozymes, with inhibition constants in the range of 96-5200nM against hCA I, of 80-670nM against hCA II, and of 195-9280nM against hCA IX, respectively. Remarkably, some derivatives, such as 3-bromophenyl-difluoromethanesulfonamide, showed a trend to selectively inhibit the mitochondrial isoform CA VA, showing selectivity ratios for inhibiting CA VA over CA II of 3.53; over CA I of 6.84 and over CA IX of 9.34, respectively, although it is a moderate inhibitor (K(I) of 160nM). Some of these derivatives may be considered as leads for the design of isozyme selective CA inhibitors targeting the mitochondrial isozyme CA VA, with potential use as anti-obesity agents.
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cecchi
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Bryan
authors.initials: B
authors.lastname: Hill
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000187:drug effects; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D024404:Carbonic Anhydrase V / Q000037:antagonists & inhibitors; D002256:Carbonic Anhydrases / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D006845:Hydrocarbons, Fluorinated; D007527:Isoenzymes; D013449:Sulfonamides; C102075:difluoromethane; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D024404:Carbonic Anhydrase V; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases