Department of Chemistry, Faculty of Science, Albaha University, Albaha, Saudi Arabia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Bioorg Med Chem. 2021 May 15;38:116136. doi: 10.1016/j.bmc.2021.116136. Epub 2021 Apr 20.
Natural product produced by plants has been the backbone for numerous anticancer agents. In the present work, natural bioactive thymol based 1,2,3-triazole hybrids have been synthesized and evaluated for anticancer activity in MCF-7 and MDA-MB-231 cancer cells. The synthesized molecules displayed desired pharmacokinetic predictions for an orally available drug. Among the synthesized hybrids, compound 4-((2-isopropyl-5-methylphenoxy)methyl)-1-o-tolyl-1H-1,2,3-triazole (10) was the most potent (IC 6.17 μM) showing comparable cytotoxity to tamoxifen (IC 5.62 μM) and 3.2 fold inhibition to 5-fluorouracil (IC 20.09 μM) against MCF-7 cancer cells. Whereas against MDA-MB-231 cancer cells, compound 10 (IC 10.52 μM) and 3-(4-((2-isopropyl-5-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (12) (IC 11.41 μM) displayed 1.42 and 1.3 fold inhibition, respectively to tamoxifen (IC 15.01 μM) whereas 2.4 fold and 2.2 activity to 5-Florouracil (IC 25.31 μM). Furthermore, 10 and 12 significantly inhibited thymidylate synthase enzyme with 2.4 and 1.26 fold activity to standard drug, Pemetrexed (IC 5.39 μM) suggesting their mode of action as thymidylate synthase inhibitors. Cell cycle arrest and annexin V induced apoptosis study of compound 10 showed cell cycle arrest at the G2/M phase and induction of apoptosis in MCF-7 cells. The molecular docking was accomplished onto thymidylate synthase (TS) protein. The active compounds exhibited promising binding interactions and binding affinities into active sites. Finally, density functional theory (DFT) calculations including chemical reactivity and molecular electrostatic potential (MEP) have been performed to confirm the data obtained from docking and biological experiments. The results from this study inferred that compound 10 could be served as a lead molecule for the treatment of breast cancer.
植物产生的天然产物一直是众多抗癌药物的支柱。在本工作中，合成了基于天然生物活性百里酚的 1,2,3-三唑杂合体，并评估了它们在 MCF-7 和 MDA-MB-231 癌细胞中的抗癌活性。合成的分子显示出对口服药物的所需药代动力学预测。在所合成的杂合体中，化合物 4-((2-异丙基-5-甲基苯氧基)甲基)-1-对甲苯基-1H-1,2,3-三唑（10）是最有效的（IC 6.17 μM），其细胞毒性与他莫昔芬（IC 5.62 μM）相当，对 MCF-7 癌细胞的抑制作用比 5-氟尿嘧啶（IC 20.09 μM）高 3.2 倍。而对 MDA-MB-231 癌细胞，化合物 10（IC 10.52 μM）和 3-(4-((2-异丙基-5-甲基苯氧基)甲基)-1H-1,2,3-三唑-1-基)苯甲酸（12）（IC 11.41 μM）分别对他莫昔芬（IC 15.01 μM）表现出 1.42 和 1.3 倍的抑制作用，对 5-氟尿嘧啶（IC 25.31 μM）的抑制作用分别为 2.4 倍和 2.2 倍。此外，化合物 10 和 12 显著抑制胸苷酸合酶酶，对标准药物培美曲塞（IC 5.39 μM）的活性分别为 2.4 和 1.26 倍，表明其作用模式为胸苷酸合酶抑制剂。化合物 10 对 MCF-7 细胞的细胞周期阻滞和膜联蛋白 V 诱导凋亡研究表明，细胞周期阻滞在 G2/M 期，并诱导 MCF-7 细胞凋亡。完成了对胸苷酸合酶（TS）蛋白的分子对接。活性化合物表现出有希望的结合相互作用和结合亲和力进入活性位点。最后，进行了密度泛函理论（DFT）计算，包括化学反应性和分子静电势（MEP），以确认对接和生物实验获得的数据。这项研究的结果表明，化合物 10 可以作为治疗乳腺癌的先导化合物。
