1. Flavones and structurally related 4-chromenones inhibit carbonic anhydrases by a different mechanism of action compared to coumarins
- Author
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Alfonso Maresca, Jean-Yves Winum, Andrea Scozzafava, Valentina Onnis, Claudiu T. Supuran, Gianfranco Balboni, Cenzo Congiu, Annalisa Maietti, Dipartimento di Scienze della Vita e dell'Ambiente, Universita degli Studi di Cagliari [Cagliari], Laboratorio di Chimica Bioinorganica (LCBI), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Inhibitor ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Thio ,Coumarin ,Hydroxylation ,01 natural sciences ,Biochemistry ,Flavones ,Carbonic anhydrase ,Flavone ,Resveratrol ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Coumarins ,Drug Discovery ,medicine ,Humans ,Protein Isoforms ,Structure–activity relationship ,Benzopyrans ,Carbonic Anhydrase Inhibitors ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,010405 organic chemistry ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Organic Chemistry ,Active site ,0104 chemical sciences ,Enzyme ,chemistry ,Mechanism of action ,biology.protein ,Molecular Medicine ,medicine.symptom - 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.
- Published
- 2012
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