Carbonic anhydrase inhibitors: Inhibition of the new membrane-associated isoform XV with phenols.
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.
Innocenti
Alessio
A
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Hilvo
Mika
M
Scozzafava
Andrea
A
Parkkila
Seppo
S
Supuran
Claudiu T
CT
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
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D010636:Phenols; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; C507974:carbonic anhydrase XV, mouse