Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isoforms I and II and transmembrane, tumor-associated isoforms IX and XII with boronic acids.
A series of aromatic, arylalkenyl- and arylalkyl boronic acids were assayed as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, and the transmembrane, tumor-associated hCA IX and XII. The best hCA I and II inhibitor was biphenyl boronic acid with, a K(I) of 3.7-4.5 microM, whereas the remaining derivatives showed inhibition constants in the range of 6.0-1560 microM for hCA I and of 6.0-1050 microM for hCA II, respectively. hCA IX and XII were effectively inhibited by most of the aromatic boronic acids (K(I)s of 7.6-12.3 microM) whereas the arylalkenyl and aryl-alkyl derivatives generally showed weaker inhibitory properties (K(I)s of 34-531 microM). The nature of the moiety substituting the boronic acid group strongly influenced the CA inhibitory activity, with inhibitors possessing low micromolar to millimolar activity being detected in this small series of investigated compounds. This study proves that the B(OH)(2) moiety represents a new zinc-binding group for the generation of effective CA inhibitors targeting isoforms with medicinal chemistry applications. The boronic acids probably bind to the Zn(II) ion within the CA active site leading to a tetrahedral geometry of the metal ion and of the B(III) derivative.
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
Jean-Yves
JY
Winum
Alessio
A
Innocenti
Andrea
A
Scozzafava
Jean-Louis
JL
Montero
Claudiu T
CT
Supuran
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry*; 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 / Q000138:chemical synthesis / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000201:enzymology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D000951:Antigens, Neoplasm; D001897:Boronic Acids; D002257:Carbonic Anhydrase Inhibitors; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; D015032:Zinc