title: Carbonic anhydrase inhibitors: inhibition of the transmembrane isozyme XIV with sulfonamides.
abstract: The inhibition of the last human carbonic anhydrase (CA, EC 4.2.1.1) isozyme (hCA XIV) discovered has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and zonisamide), as well as the sulfamate antiepileptic drug topiramate. The full-length hCA XIV is an enzyme showing a medium-low catalytic activity, quite similar to that of hCA XII, with the following kinetic parameters at 20 degrees C and pH 7.5, for the CO2 hydration reaction: k(cat) = 3.12 x 10(5) s(-1) and k(cat)/K(M) = 3.9 x 10(7) M(-1) s(-1). All types of activities have been detected for the investigated compounds, with several micromolar inhibitors, including zonisamide, topiramate, and simple sulfanilamide derivatives (K(I)-s in the range of 1.46-6.50 microM). In addition, topiramate and zonisamide were observed to behave as weak hCA XII inhibitors, while zonisamide was an effective hCA IX inhibitor (K(I) of 5.1 nM). Some benzene-1,3-disulfonamide derivatives or simple five-membered heteroaromatic sulfonamides showed K(I)-s in the range of 180-680 nM against hCA XIV, whereas the most effective of such inhibitors, including 3-chloro-/bromo-sulfanilamide, benzolamide-like, ethoxzolamide-like, and acetazolamide/methazolamide-like derivatives, showed inhibition constant in the range of 13-48 nM. The best hCA XIV inhibitor was aminobenzolamide (K(I) of 13 nM), but no CA XIV-selective derivatives were evidenced. There are important differences of affinity of these sulfonamides/sulfamates for the three transmembrane CA isozymes, with CA XII showing the highest affinity, followed by CA IX, whereas CA XIV usually showed the lowest affinity for these inhibitors.
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Nishimori
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Antonio
authors.initials: A
authors.lastname: Mastrolorenzo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects*; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D000077236:Topiramate
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D008565:Membrane Proteins; D013449:Sulfonamides; D000077236:Topiramate; D005632:Fructose; D002256:Carbonic Anhydrases; C466621:carbonic anhydrase XIV