title: Carbonic anhydrase inhibitors: Inhibition of the new membrane-associated isoform XV with phenols.
abstract: Inhibition of the newest isoform of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA XV, with a series of phenols was investigated. Murine CA XV showed an inhibition profile by phenols distinct of those of the cytosolic human isoforms CA I and II. Phenol and some of its 2-, 3-, and 4-substituted derivatives incorporating hydroxy, fluoro, carboxy, and acetamido moieties were effective CA XV inhibitors, with inhibition constants in the range of 7.20-11.30 microM, whereas compounds incorporating 4-amino-, 4-cyano, or 3-hydroxy groups were less effective (K(I)s of 335-434 microM). The best phenol inhibitor was clioquinol (K(I) of 2.33 microM). Phenols show a different inhibition mechanism as compared to sulfonamides and their isosteres, and may lead to the design of compounds with selectivity for inhibiting different CA isozymes with medicinal chemistry applications.
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: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Mika
authors.initials: M
authors.lastname: Hilvo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D010636:Phenols; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; C507974:carbonic anhydrase XV, mouse