Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
Bioorg Chem. 2020 Aug;101:103995. doi: 10.1016/j.bioorg.2020.103995. Epub 2020 Jun 3.
Novel azole derivatives 3-30 were designed, synthesized, and screened for their antitumor activity on HepG2 cell line. The cytotoxicity screening demonstrated that imidazolone 8 and triazoles 25 and 29 exhibited more potent cytotoxic activities by 1.21-, 4.75-, and 1.8-fold compared to Sorafenib (SOR). Furthermore, vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme inhibition assay declared that compounds 25 and 29 had inhibitory activity at the nanomolar concentration. Moreover, the tested compounds exhibited good β-tubulin (TUB) polymerization inhibition percentages. In addition, DNA flow cytometry analysis over HepG2 cells indicated that triazoles 25 and 29 demonstrated arrest at G and G/M phase of the cell cycle and induced apoptotic activity by increasing sub-G phase. Finally, mechanistic studies of the proapoptotic activities of compounds 8, 10, 11, 25, and 29 indicated that they induced upregulation of P53, Fas/Fas-ligand, and BAX/BCL-2 ratio expression that resulted in increasing the active caspase 3/7 percentages and trigger apoptosis.
新型唑类衍生物 3-30 被设计、合成并筛选其对 HepG2 细胞系的抗肿瘤活性。细胞毒性筛选表明，咪唑酮 8 和三唑 25 和 29 的细胞毒性比索拉非尼（SOR）分别强 1.21 倍、4.75 倍和 1.8 倍。此外，血管内皮生长因子受体-2（VEGFR-2）酶抑制试验表明，化合物 25 和 29 在纳摩尔浓度下具有抑制活性。此外，测试的化合物表现出良好的β-微管蛋白（TUB）聚合抑制百分比。此外，用 DNA 流式细胞术分析 HepG2 细胞表明，三唑 25 和 29 可使细胞周期的 G 和 G/M 期停滞，并通过增加亚 G 期诱导细胞凋亡活性。最后，化合物 8、10、11、25 和 29 的促凋亡活性的机制研究表明，它们诱导 P53、Fas/Fas 配体和 BAX/BCL-2 比值的上调，导致活性 caspase 3/7 百分比增加并触发凋亡。
