ABSTRACT
Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA-telomerase dual-hybrid inhibitors. Compounds 1b, 7b, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with KI values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC50 values ranging from 5.2 to 9.1 µM). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Telomerase/antagonists & inhibitors , Zidovudine/chemistry , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase II/chemistry , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrase Inhibitors/pharmacology , Catalytic Domain , Crystallography, X-Ray , Cycloaddition Reaction , Drug Design , HT29 Cells , Humans , PC-3 Cells , Structure-Activity Relationship , Telomerase/genetics , Telomerase/metabolism , Triazoles/chemistryABSTRACT
A series of 2-thio- and 2-seleno-acetamides bearing the benzenesulfonamide moiety were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against different pathogenic bacteria such as the Vibrio cholerae (VchCA-α and VchCA-ß), Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ), Mycobacterium tuberculosis (Rv3723-ß) and the Salmonella enterica serovar Typhimurium (StCA2-ß). The molecules represent interesting leads worth developing as innovative antibacterial agents since they possess new mechanism of action and isoform selectivity preferentially against the bacterial expressed CAs. The identification of potent and selective inhibitors of bacterial CAs may lead to tools also useful for deciphering the physiological role(s) of such proteins.
Subject(s)
Acetamides/chemistry , Bacteria/drug effects , Bacteria/pathogenicity , Bacterial Infections/drug therapy , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/chemistry , Sulfonamides/chemistry , Bacteria/enzymology , Bacterial Infections/microbiology , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Organoselenium Compounds/chemistry , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Sulfonamides/pharmacology , BenzenesulfonamidesABSTRACT
A novel series of thio- and seleno-acetamides bearing benzenesulfonamide were synthetized and tested as human carbonic anhydrase inhibitors. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX/XII). Several derivatives showed potent inhibition activity in low nanomolar range such as 3a, 4a, 7a and 8a. Furthermore, based on the tail approach we explain the interesting and selective inhibition profile of compound such as 5a and 9a, which were more selective for hCA I, 9b which was selective for hCA II, 3f selective for hCA IX and finally, 3e and 4b selective for hCA XII, over the other three isoforms. They are interesting leads for the development of more effective and isoform-selective inhibitors.
