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Carbonic anhydrase inhibitors: Inhibition of cytosolic isozymes I and II with sulfamide derivatives

Casini, Angela, Winum, JY, Montero, JL, Scozzafava, A and Supuran, CT 2003. Carbonic anhydrase inhibitors: Inhibition of cytosolic isozymes I and II with sulfamide derivatives. Bioorganic & Medicinal Chemistry Letters 13 (5) , pp. 837-840. 10.1016/S0960-894X(03)00028-3

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Elsevier
ISSN: 0960-894X
Date of Acceptance: 20 December 2002
Last Modified: 04 Jun 2017 08:49
URI: http://orca.cf.ac.uk/id/eprint/85551

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