Synthesis and inhibition potency of novel ureido benzenesulfonamides incorporating GABA as tumor-associated carbonic anhydrase IX and XII inhibitors

Abstract

New ureido benzenesulfonamides incorporating a GABA moiety as a linker between the ureido and the sulfonamide functionalities were synthesized and their inhibition potency determined against both the predominant cytosolic (hCA I and II) and the transmembrane tumor-associated (hCA IX and XII) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The majority of these compounds were medium potency inhibitors of the cytosolic isoform hCA I and effective hCA II inhibitors, whereas they showed strong inhibition of the two transmembrane tumor-associated isoforms hCA IX and XII, with K_Is in nanomolar range. Only one derivative had a good selectivity for inhibition of the tumor-associated hCA IX target isoform over the cytosolic and physiologically dominant off-target hCA I and II, being thus a potential tool to develop new anticancer agents.

• Anticancer agents
• carbonic anhydrase inhibitors
• GABA linker
• transmembrane isoforms
• ureido benzenesulfonamide

Declaration of interest

Most of the authors declare no financial interest. CTS reports conflict of interest as author of many patents on CA inhibitors.

This project was funded by a 7th FP EU grant (METOXIA). MC and CTS also thank the Erasmus project for a mobility grant.

Supplementary material available online

Supplemental Information.