Synthesis of a new series of N⁴-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII

Abstract

A series of novel N(4)-substituted 4-(2-aminoethyl)benzenesulfonamides 5-17 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human CA I investigated compounds displayed KI values from 96.3 to 3520 nM, toward hCA II at range of 18.1-2055 nM, while against hCA IX ranging from 5.9 to 419 nM and against hCA XII in the range of 4.0-414 nM. The very good inhibitory activity against tumor-associated hCA IX and hCA XII was found. The six new compounds displayed a powerful inhibitory potency toward hCA IX (K(I) = 5.9-10.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). The most potent hCA IX and hCA XII inhibitors 11 and 12 (K(I): 5.9 and 6.2 nM for hCA IX and 4.3 and 4.0 nM for hCA XII, respectively) belonged to the compounds with cationic character and presented meaningful affinity to the transmembrane isoforms hCA IX and XII than to physiologically dominant isozymes hCA I and II with the selectivity ratios hCA IX versus hCA II and hCA XII versus hCA II for 11 and 12 in the range of 10-15.

Keywords: Carbonic anhydrase isozymes I, II, IX and XII inhibitors; Sulfonamide; Synthesis.