title: Carbonic anhydrase inhibitors. Inhibition of isozymes I, II, IV, V and IX with complex fluorides, chlorides and cyanides.
abstract: The inhibition of five human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, the membrane-bound hCA IV, the mitochondrial hCA V and the tumour associated, transmembrane hCA IX, with complex anions incorporating fluoride, chloride and cyanide, as well as B(III), Si(IV), P(V), As(V), Al(III), Fe(II), Fe(III), Pd(II), Pt(II), Pt(IV), Cu(I), Ag(I), Au(I) and Nb(V) species has been investigated. Apparently, the most important factors influencing activity of these complexes are the nature of the central metal ion/element, and its charge. Geometry of these compounds appears to be less important, since both linear, tetrahedral, octahedral as well as pentagonal bipyramidal derivatives led to effective inhibitors. However, the five isozymes showed very different affinities for these anion inhibitors. The best hCA I inhibitors were cyanide, dicyanocuprate and dicyanoaurate (K(I)s in the range of 0.5-7.7 microM), whereas the least effective were fluoride and hexafluoroarsenate. The best hCA II inhibitors were cyanide, hexafluoroferrate and tetrachloroplatinate (K(I)s in the range of 0.02-0.51 mM), whereas the most ineffective ones were fluoride, hexafluoroaluminate and chloride. The best hCA IV inhibitors were dicyanocuprate (K(I) of 9.8 microM) and hexacyanoferrate(II) (K(I) of 10.0 microM), whereas the worst ones were tetrafluoroborate and hexafluoroaluminate (K(I)s in the range of 124-126 mM). The most effective hCA V inhibitors were cyanide, heptafluoroniobate and dicyanocuprate (K(I)s in the range of 0.015-0.79 mM), whereas the most ineffective ones were fluoride, chloride and tetrafluoroborate (K(I)s in the range of 143-241 mM). The best hCA IX inhibitors were on the other hand cyanide, heptafluoroniobate and dicyanoargentate (K(I)s in the range of 4 microM-0.33 mM), whereas the worst ones were hexacyanoferrate(III) and hexacyanoferrate(II).
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Jochen
authors.initials: J
authors.lastname: Antel
authors.forename: Michael
authors.initials: M
authors.lastname: Wurl
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Firnges
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000838:Anions / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000378:metabolism; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D030741:Carbonic Anhydrase IV / Q000037:antagonists & inhibitors; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D024404:Carbonic Anhydrase V / Q000037:antagonists & inhibitors; D002256:Carbonic Anhydrases / Q000378:metabolism; D002712:Chlorides / Q000737:chemistry* / Q000494:pharmacology; D003486:Cyanides / Q000737:chemistry* / Q000494:pharmacology; D005459:Fluorides / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000838:Anions; D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D002712:Chlorides; D003486:Cyanides; D007527:Isoenzymes; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV; D024404:Carbonic Anhydrase V; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D005459:Fluorides