Abstract
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•New series thiazole-based chalcones and 4-hetarylthiazoles were designed and synthesized.•Cytotoxicity was evaluated against HepG2, A549 and MCF-7 cell lines.•Compounds 3a arrested cell cycle at G2/M phase with induction of apoptosis.•Compounds 3a, 3d, 3e, 7a inhibited CDK1, CDK2 and CDK4.•Compounds 3a,3d,3e,7a elevated Bax, caspase-3, P53 levels and decreased Bcl-2 level.
The crucial need for novel antitumor agents with high selectivity toward cancer cells has promoted us to synthesize new series of thiazole-based chalcones and 4-hetarylthiazoles (rigid chalcones). The synthesis of thiazolyl chalcones and 4-hetarylthiazoles and the assertion of their structure are described. Their anti-proliferative activity was estimated against three human cancer cell lines; HepG-2, A549 and MCF-7. 3-(4-Methoxyphenyl)-1-(5-methyl-2-(methylamino)thiazol-4-yl)prop-2-en-1-one (chalcone derivative 3a) showed significant and broad antitumor activity that was more potent than Doxorubicin. In addition, compounds 3d, 3e and 7a displayed potent activity compared to Doxorubicin. Additionally, these compounds were less toxic on normal lung cells WI-38 with high selectivity index. Further study on 3a regarding its effect on the normal cell cycle profile in A549 cells demonstrated cell cycle arrest at the G2/M phase together with rise in the percentage of the apoptotic pre-G1 cells. CDK1/CDK2/CDK4 inhibition assays were carried out on 3a, 3d, 3e and 7a and the results revealed non selective inhibition on the tested CDKs with IC50 values of 0.78–1.97 µM. Moreover, docking study predicted that 3a, 3d, 3e and 7a can fit in the ATP binding site of CDK1 enzyme. The apoptosis induction potential of 3a, 3d, 3e and 7a was also estimated against some apoptosis markers. Interestingly, they elevated the level of Bax by 6.36–10.12 folds and reduced the expression of Bcl-2 by 1.94–4.12 folds compared to the control. Furthermore, they increased both active caspase-3 and p53 levels by 8.76–10.56 and 6.85–10.36 folds, respectively higher than the control which indicates their potential to induce apoptosis.