Carbonic anhydrase inhibitors. Selective inhibition of human tumor-associated isozymes IX and XII and cytosolic isozymes I and II with some substituted-2-mercapto-benzenesulfonamides

Abstract

A series of 2-mercapto-substituted-benzenesulfonamides has been prepared by a unique two-step procedure starting from the corresponding 2-chloro-substituted benzenesulfonamides. Compounds bearing an unsubstituted mercapto group and the corresponding S-benzoyl derivatives were investigated as inhibitors of four isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), i.e., the cytosolic, ubiquitous isozymes CA I and II, as well as the transmembrane, tumor associated isozymes CA IX and XII. These derivatives were medium potency hCA I inhibitors (K_Is in the range of 1.5–5.7 μM), two derivatives were strong hCA II inhibitors (K_Is in the range of 15–16 nM), whereas the others showed weak activity. These compounds inhibited hCA IX with inhibition constants in the range 160–1950 nM and hCA XII with inhibition constants in the range 1.2–413 nM. Some of these derivatives showed a certain degree of selectivity for inhibition of the tumor-associated over the cytosolic isoforms, being thus interesting leads for the development of potentially novel applications in the management of hypoxic tumors which overexpress CA IX and XII.

Keywords::

• Carbonic anhydrase
• isozymes
• inhibition
• CA I
• CA II
• CA IX

Acknowledgement

This work was supported in part by an EU grant (to CTS and AS) of the 6th framework program (EUROXY project).