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.

中文翻译：

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基于噻唑的查耳酮和4-杂芳基噻唑作为有效的抗癌剂的发现：合成，对接研究和抗癌活性。

对癌细胞具有高选择性的新型抗肿瘤药的迫切需求促使我们合成了一系列新的基于噻唑的查耳酮和4-杂芳基噻唑（刚性查耳酮）。描述了噻唑基查耳酮和4-杂芳基噻唑的合成及其结构的主张。估计它们对三种人类癌细胞系的抗增殖活性。HepG-2，A549和MCF-7。3-（4-甲氧基苯基）-1-（5-甲基-2-（甲基氨基）噻唑-4-基）丙-2-烯-1-酮（查耳酮衍生物3a）显示出显着而广泛的抗肿瘤活性，更有效比阿霉素。另外，与阿霉素相比，化合物3d，3e和7a显示出有效的活性。另外，这些化合物对具有高选择性指数的正常肺细胞WI-38的毒性较小。关于3a对A549细胞中正常细胞周期谱的影响的进一步研究表明，细胞周期停滞在G2 / M期，并且凋亡前G1细胞的百分比增加。在3a，3d，3e和7a上进行了CDK1 / CDK2 / CDK4抑制试验，结果显示对测试的CDK进行非选择性抑制，IC50值为0.78-1.97 µM。此外，对接研究预测3a，3d，3e和7a可以适合CDK1酶的ATP结合位点。还针对某些凋亡标记物估计了3a，3d，3e和7a的凋亡诱导潜力。有趣的是，与对照相比，他们将Bax的水平提高了6.36-10.12倍，并将Bcl-2的表达降低了1.94-4.12倍。此外，它们将活性caspase-3和p53的水平提高了8.76-10.56和6.85-10.36倍，