Carbonic anhydrase inhibitors: inhibition of cytosolic isozymes I and II with sulfamide derivatives.
A novel class of effective CAIs has been identified, starting from a very weak carbonic anhydrase inhibitor (CAI), sulfamide, whose X-ray crystal structure in the adduct with hCA II has recently been reported. A series of N,N-disubstituted- and N-substituted-sulfamides were prepared from the corresponding amines and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide or the unstable N-(tert-butoxycarbonyl)sulfamoyl chloride. The disubstituted compounds being too bulky, were ineffective as CAIs, whereas mono-substituted derivatives (incorporating aliphatic, cyclic and aromatic moieties) as well as a bis-sulfamide, behaved as micro-nanomolar inhibitors of two cytosolic isozymes, hCA I and hCA II, responsible for critical physiological processes in higher vertebrates. Aryl-sulfamides were more effective than aliphatic derivatives. Low nanomolar inhibitors have been detected, which generally incorporated 4-substituted phenyl moieties in their molecule. This is the first example of CAIs in which low nanomolar inhibitors were generated starting from a very ineffective lead molecule.
Casini
Angela
A
Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy.
Winum
Jean-Yves
JY
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000588:Amines / Q000737:chemistry; D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
D000588:Amines; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II