Marine College, Shandong University, Weihai 264209, China; Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium.
Marine College, Shandong University, Weihai 264209, China.
Bioorg Chem. 2019 Jul;88:102951. doi: 10.1016/j.bioorg.2019.102951. Epub 2019 Apr 27.
Oleanolic acid (OA) and glycyrrhetinic acid (GA) are natural products with anticancer effects. Cinnamic acid (CA) and its derivatives also exhibited certain anticancer activity. In order to improve the anticancer activity of OA and GA, we designed and synthesized a series of novel OA-CA ester derivatives and GA-CA ester derivatives by using molecular hybridization approach. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to assess their in vitro cytotoxicity on three cell lines (HeLa (cervical cancer), MCF-7 (breast cancer) and L-O2 (a normal hepatic cell)). Among the evaluated compounds, 3o presented the strongest selective cytotoxicity on HeLa cells (IC = 1.35 μM) and showed no inhibitory activity against MCF-7 cells (IC > 100 μM) and L-O2 cells (IC > 100 μM), and 3e presented the strongest selective inhibition of the MCF-7 cells (IC = 1.79 μM). What's more, compound 2d also showed very strong selective inhibitory activity against HeLa cells (IC = 1.55 μM). The further research using Hoechst 33342, AO/EB dual-staining, flow cytometric analysis and DCFH-DA fluorescent dye staining assay presented that 2d and 3o could induce HeLa cells apoptosis and autophagy.
齐墩果酸（OA）和甘草次酸（GA）是具有抗癌作用的天然产物。肉桂酸（CA）及其衍生物也表现出一定的抗癌活性。为了提高 OA 和 GA 的抗癌活性，我们采用分子杂交的方法设计并合成了一系列新型 OA-CA 酯衍生物和 GA-CA 酯衍生物。采用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法评估了它们对三种细胞系（HeLa（宫颈癌）、MCF-7（乳腺癌）和 L-O2（正常肝细胞））的体外细胞毒性。在所评价的化合物中，3o 对 HeLa 细胞表现出最强的选择性细胞毒性（IC=1.35μM），对 MCF-7 细胞（IC>100μM）和 L-O2 细胞（IC>100μM）没有抑制活性，而 3e 对 MCF-7 细胞的抑制作用最强（IC=1.79μM）。此外，化合物 2d 对 HeLa 细胞也表现出非常强的选择性抑制活性（IC=1.55μM）。进一步使用 Hoechst 33342、AO/EB 双重染色、流式细胞术分析和 DCFH-DA 荧光染料染色实验表明，2d 和 3o 可诱导 HeLa 细胞凋亡和自噬。
