Synthesis and Evaluation Of Carbonic Anhydrase VII/IX Inhibitor Properties Of a Group Of Taurinamidobenzensulfonamide Derivatives Designed By Tail Approach
Project no. 340 · Status: Kapanmış · 2018
Summary
Some of carbonic anhydrase isozymes are recognised as drug targets for the treatment of glaucoma (hCA II, hCA IV, and hCA XII), cancer (hCA IX and hCA XII), obesity (hCA VA), and epilepsy (hCA VII). The selective inhibiton of these drug targets offers a different mechanism of action in the treatment of epilepsy and cancer. In this study, the classical CA inhibitors functionalised with taurine aminoacid which is well known for its anticonvulsant and anticancer activities by utilising tail approach method. For this aim, the sulfonic acid part of taurine functionalized as sulfonamide with sulfanilamide and its congeners. The amino function connected to substituted aromatic rings via amide, urea and thiourea linkage. All final compounds were characterized by means of spectroscopy and ESI-MS, and were pure as determined by elemental analysis. All the synthesized compounds were investigated for their ability to inhibit the CAs I, II, VII, IX and XII by means of the stopped flow CO2 hydrase assay. In general all compounds tested has the ability to inhibit all the isomers with nM Ki values. None of the compounds displayed selective inhibition against CA VII isomer. The variations of functional groups (urea, thiourea and amide) and lenght of the molecules was found to have an impact on inhibitory potencies. Among the amide derivatives, 3 of them displayed selective inhibition against CA XII. Most of the thiourea compounds showed a Ki value below 100 nM against all of the isozymes. 4-((2-(3-(4-fluorophenyl)ureido)ethyl)sulfonamido)benzene sulfonamide (U3) derivative was the only final compund which posses selective inhibition profile against CA IX and showed stronger inhibition of CA IX compared to the reference drug acetozolamide. U3 emerged as the most promising inhibitor of the tumor-associated isoforms CA IX and CA XII with an impressive hCA II/hCA IX (52) and hCA II/hCA XII (16) selectivity index, The results of this study may shed light to design more selective inhibitors which will have different mechanism of action compared to the classical anti-cancer agents.