Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Med Chem. 2012 Mar;8(2):151-62. doi: 10.2174/157340612800493719.
Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.
大多数癌症化疗药物和化学预防药物通过触发细胞凋亡来发挥作用。在这项研究中，合成了新的苯并咪唑和苯并噻唑衍生物，以在初步筛选研究后研究它们对 HepG2 肝癌细胞系的影响。构建了剂量反应曲线，并进一步研究了最活跃的衍生物进行凋亡分析。与对照组相比，六种活性苯并咪唑衍生物（8、9、10、12、13 和 14）显著诱导了细胞凋亡。两种化合物 10 和 12 通过将细胞周期的 G1 期阻滞来诱导细胞凋亡，这通过增加 p21 的表达水平得到证实。在存在和不存在测试衍生物的情况下，测定了众所周知的凋亡关键执行者之一的 caspase-3 的活性。我们的结果表明，与对照组相比，化合物 10 和 12 显著增加了 caspase-3 的活性。此外，使用分子操作环境模块获得了化合物 10 和 12 与 caspase-3 活性位点结合的对接构象。这项研究表明，苯并咪唑衍生物 10 和 12 引起肝癌细胞 HepG2 的细胞毒性并诱导细胞凋亡。
