Carbonic anhydrase inhibitors: Inhibition of the tumor-associated isozymes IX and XII with polyfluorinated aromatic/heterocyclic sulfonamides.
The tumor-associated transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX (CA IX) and XII (CA XII) are involved in acidification of hypoxic tumors, a process correlated with poor prognosis and clinical outcome of patients harboring such tumors. This process may be reversed by inhibiting these enzymes with potent sulfonamide/sulfamate inhibitors. A series of such aromatic/heterocyclic sulfonamides incorporating 2,3,5,6-tetrafluorobenzoyl-, 2,3,5,6-tetrafluorophenylsulfonyl- and pentafluorophenylureido moieties has been investigated for its interaction with the catalytic domain of the human isozymes hCA IX and hCA XII. Some of these compounds showed excellent inhibitory properties against both isozymes IX and XII, with several subnanomolar inhibitors detected for the first time. These sulfonamides may constitute valuable candidates for the development of novel antitumor therapies based on the inhibition of such tumor-associated CA isozymes.
Pastorekova
Silvia
S
Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 842 45 Bratislava, Slovak Republic.
Vullo
Daniela
D
Casini
Angela
A
Scozzafava
Andrea
A
Pastorek
Jaromir
J
Nishimori
Isao
I
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005465:Fluorocarbon Polymers / Q000737:chemistry; D006571:Heterocyclic Compounds; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D005465:Fluorocarbon Polymers; D006571:Heterocyclic Compounds; D007527:Isoenzymes; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII