title: Coumarins incorporating hydroxy- and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II.
abstract: A series of coumarins incorporating hydroxy-, chloro- and/or chloromethyl-moieties in positions 3-, 4-, 6- and 7- of the heterocyclic ring were investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the house-keeping, offtarget isoforms CA I and II, but showed effective, submicromolar inhibition of the transmembrane, tumor-associated isoforms CA IX and XII. The nature and position of the groups substituting the coumarin ring greatly influenced CA inhibitory properties. 6-Hydroxycoumarin showed K(I)s >100 microM against CA I and II, of 0.198 microM against CA IX and of 0.683 microM against CA XII, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic isoforms. These compounds are also excellent leads for designing isoform-selective enzyme inhibitors.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Firenze), Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000201:enzymology*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII