Synthesis of new thiazole derivatives and investigation of the mechanisms of their anticancer action

In this study, new thiazolyl hydrazone derivatives (2a-l) were synthesized and their cytotoxic activities towards A549 human lung adenocarcinoma and CCD-19Lu human lung fibroblast cell lines were evaluated. The effects of the compounds with selective anticancer activity on apoptosis, caspase-3 and Akt were also investigated. It was determined that trifluoromethyl-substituted compound 2g (IC50= 3.37±0.15 µM), cyano-substituted compound 2c (IC50= 4.47±0.90 µM) and chloro-substituted compound 2e (IC50= 5.23±0.45 µM) showed more selective and strong anticancer activity against A549 cells than cisplatin (IC50= 6.97±2.61 µM). In particular, 2-(2-([2,2'-bithiophen]-5-ylmethylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (2c) induced apoptosis more strongly and caused more caspase-3 activation in A549 cells compared to cisplatin. Moreover, compound 2c (IC50= 0.46±0.03 µM) showed much stronger Akt inhibitory activity than Akt inhibitor GSK690693 (IC50= 4.97±0.06 µM). According to the molecular docking study, this compound formed strong interactions with Trp80 amino acid residue with high affinity for the Akt substrate binding site. It has been determined that compound 2c, which is predicted as a drug candidate endowed with a good pharmacokinetic profile and high oral bioavailability, exerts its in vitro cytotoxic and apoptotic effects on A549 cell line through Akt inhibition.