Synthesis and investigation of selective human carbonic anhydrase IX, XII inhibitors using coumarins bearing a sulfonamide or biotin moiety

Abstract

The role of carbonic anhydrases isoforms (CAs) IX and XII in the pathogenesis and progression of many types of solid tumors is well known. In this context, selective CA inhibitors (CAIs) towards the mentioned isoforms is a validated strategy for the development of agents to target cancer. For this purpose, novel coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds were synthesized and tested as inhibitors of four different human carbonic anhydrases isoforms: hCA I, II, IX and XII. Coumarin-sulfonamide derived 27, with a thiourea moiety and triazole as linker, showed the highest inhibition activity against hCA XII with an inhibition constant (K_I) of 7.5 nM and afforded a very good selectivity over hCA I. Compound 32 was the most potent inhibitor against hCA IX (K_I = 6.3 nM), 4-fold stronger than the drug acetazolamide AAZ (K_I = 25 nM), used herein as a reference compound, and showed remarkable selectivity over hCA I and II. The coumarin-biotin derivatives 37–39 showed outstanding selectivity towards on-target enzymes (hCA IX and XII) and appear as plausible leads for designing of CAIs.