Carbonic anhydrase activators: activation of human isozymes I, II and IX with phenylsulfonylhydrazido l-histidine derivatives.
Activation of the human carbonic anhydrase (CA, EC 4.2.1.1) isozymes I, II (cytosolic) and IX (transmembrane, tumor-associated isoform) with a series of arylsulfonylhydrazido-l-histidines incorporating 4-substituted-phenyl, pentafluorophenyl- and beta-naphthyl moieties was investigated. The compounds showed a weak hCA I activation profile, but were more efficient as hCA II and IX activators. The 4-iodophenyl-substituted derivative behaved as a strong and isozyme selective hCA II activator, with an activation constant of 0.21muM. This is the first isoform-selective, potent CA activator reported to date.
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.
Marie-Rose
MR
Abdo
Daniela
D
Vullo
Mohamed-Chiheb
MC
Saada
Jean-Louis
JL
Montero
Andrea
A
Scozzafava
Jean-Yves
JY
Winum
Claudiu T
CT
Supuran
D000951:Antigens, Neoplasm / Q000378:metabolism*; D024401:Carbonic Anhydrase I / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004789:Enzyme Activation; D006639:Histidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000737:chemistry
D000951:Antigens, Neoplasm; D020033:Protein Isoforms; D011994:Recombinant Proteins; C542963:phenylsulfonylhydrazido l-histidine; D006639:Histidine; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases