Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with bis-sulfamates.
A series of bis-sulfamates incorporating aliphatic, aromatic, or betulinyl moieties in their molecules was obtained by reaction of the corresponding diols/diphenols with sulfamoyl chloride. The library of bis-sulfamates thus obtained was tested for the inhibition of three physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX. The new compounds reported here inhibited hCA I with K(I) s in the range of 79 nM-16.45 microM, hCA II with K(I) s in the range of 6-643 nM, and hCA IX with K(I) s in the range of 4-5400 nM. Several low nanomolar hCA IX inhibitors were detected, such as 1,8-octylene-bis-sulfamate or 1,10-decylene-bis-sulfamate (K(I) s in the range of 4-7 nM), which showed good selectivity ratios (in the range of 3.50-3.85) for hCA IX over hCA II inhibition. The most selective hCA IX inhibitor was phenyl-1,4-dimethylene-bis-sulfamate (K(I) of 61.6 nM), which was a 10.43 times better hCA IX than hCA II inhibitor. These derivatives are interesting candidates for the development of novel antitumor therapies targeting hypoxic tumors, since hCA IX is highly overexpressed in such tissues, and its presence is correlated with bad prognosis and unfavorable clinical outcome.
Winum
Jean-Yves
JY
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Pastorekova
Silvia
S
Jakubickova
Lydia
L
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Pastorek
Jaromir
J
Vullo
Daniela
D
Innocenti
Alessio
A
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D013451:Sulfonic Acids; C005741:sulfamic acid; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases