title: Flavones and structurally related 4-chromenones inhibit carbonic anhydrases by a different mechanism of action compared to coumarins.
abstract: An inhibition study of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with flavones and aminoflavones, compounds possessing a rather similar scaffold with the coumarins, recently discovered inhibitors of this enzyme, is reported. The natural product flavone and some of its hydroxylated derivatives did not show time-dependent inhibition of the CAs, sign that they are not hydrolyzed within the enzyme active site as the (thio)coumarins and lactones. These compounds were low micromolar inhibitors of hCA I, II, IX and XII, with K(I)s in the range of 1.88-9.07 μM. A series of substituted 2-amino-3-phenyl-4H-chromen-4-ones, incorporating chloro- and methoxy substituents in various positions of the heterocycle, were then prepared and assayed as hCA I and II inhibitors, showing activity in the micromolar range. Some of these derivatives, as well as cis+trans resveratrol, were then assayed for the inhibition of all catalytically active mammalian CA isoforms, hCA I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII, XIV and mCA XV (h=human, m=murine enzyme). These derivatives inhibited these CAs in the submicromolar-low micromolar range. Flavones, although not as active as the coumarins, may be considered as interesting leads for the design of non-sulfonamide CA inhibitors.
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, I-09124 Cagliari, Italy. gbalboni@unica.it
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Annalisa
authors.initials: A
authors.lastname: Maietti
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D020033:Protein Isoforms; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D047309:Flavones; D020033:Protein Isoforms