Design and synthesis of the novel oleanolic acid-cinnamic acid ester derivatives and glycyrrhetinic acid-cinnamic acid ester derivatives with cytotoxic properties

• Published in: Bioorganic chemistry 2019-07, Vol.88, p.102951, Article 102951
• Main Authors: Wang, Rui, Yang, Wei, Fan, Yiqing, Dehaen, Wim, Li, Yang, Li, Huijing, Wang, Wei, Zheng, Qingxuan, Huai, Qiyong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Cell Line; Cell Proliferation - drug effects; Cinnamates - chemistry; Cinnamates - pharmacology; Cytotoxicity; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; Glycyrrhetinic Acid - chemistry; Glycyrrhetinic Acid - pharmacology; Glycyrrhetinic acid-cinnamic acid ester derivatives; HeLa Cells; Humans; MCF-7 Cells; Molecular Structure; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Oleanolic acid-cinnamic acid ester derivatives; Reactive Oxygen Species - analysis; Reactive Oxygen Species - metabolism; ROS; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.102951

[Display omitted] •A new series of OA-CA ester derivatives and GA-CA ester derivatives was synthesized.•Compound 3o presented the strongest selective cytotoxicity on HeLa cells.•Compound 2d also showed very strong selective inhibitory activity against HeLa cells.•Compounds 2d and 3o could induce HeLa cells apoptosis and autophagy. 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 (IC50 = 1.35 μM) and showed no inhibitory activity against MCF-7 cells (IC50 > 100 μM) and L-O2 cells (IC50 > 100 μM), and 3e presented the strongest selective inhibition of the MCF-7 cells (IC50 = 1.79 μM). What’s more, compound 2d also showed very strong selective inhibitory activity against HeLa cells (IC50 = 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.