title: Phenylethynylbenzenesulfonamide regioisomers strongly and selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic isoforms I and II.
abstract: A series of compounds incorporating regioisomeric phenylethynylbenzenesulfonamide moieties has been investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the milliomolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. The position of the sulfamoyl group with respect to the alkyne functionality, and the nature of the moieties substituting the second aromatic ring were the principal structural features influencing CA inhibition. The para-sulfamoyl-substituted derivatives were effective inhibitors of CA IX and XII, the meta-substituted regioisomers of CA I, IX and XII, whereas the ortho-substituted sulfonamides were weak inhibitors of CA I, II and IX, but inhibited significantly CA XII.
authors.affiliation: University of Alberta, Faculty of Pharmacy, Edmonton, Alberta, Canada T6G 2N8.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000951:Antigens, Neoplasm; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D007527:Isoenzymes; D013449:Sulfonamides; C513023:phenylethynylbenzenesulfonamide; D000096926:Benzenesulfonamides; C089226:CA9 protein, human; C477378:carbonic anhydrase XII