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Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors

Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels and Chemicals, Co-Innovation Center for Efficient Processing and Utilization of Forest Products, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
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Int. J. Mol. Sci. 2020, 21(8), 2876; https://doi.org/10.3390/ijms21082876
Received: 29 February 2020 / Revised: 1 April 2020 / Accepted: 15 April 2020 / Published: 20 April 2020
(This article belongs to the Section Bioactives and Nutraceuticals)
In this study, a series of new indole derivatives of ursolic acid bearing different N-(aminoalkyl)carboxamide side chains were designed, synthesized, and evaluated for their in vitro cytotoxic activities against two human hepatocarcinoma cell lines (SMMC-7721 and HepG2) and normal hepatocyte cell line (LO2) via MTT assay. Among them, compound 5f exhibited the most potent activity against SMMC-7721 and HepG2 cells with IC50 values of 0.56 ± 0.08 μM and 0.91 ± 0.13 μM, respectively, and substantially lower cytotoxicity to LO2 cells. A follow-up enzyme inhibition assay and molecular docking study indicated that compound 5f can significantly inhibit the activity of Topoisomerase IIα. Further mechanistic studies performed in SMMC-7721 cells revealed that compound 5f can elevate the intracellular ROS levels, decrease mitochondrial membrane potential, and finally lead to the apoptosis of SMMC-7721 cells. Collectively, compound 5f is a promising Topoisomerase II (Topo II) inhibitor, which exhibited the potential as a lead compound for the discovery of novel anticancer agents. View Full-Text
Keywords: ursolic acid; indole derivatives; anticancer activity; topoisomerase II; apoptosis ursolic acid; indole derivatives; anticancer activity; topoisomerase II; apoptosis
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MDPI and ACS Style

Li, A.-L.; Hao, Y.; Wang, W.-Y.; Liu, Q.-S.; Sun, Y.; Gu, W. Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors. Int. J. Mol. Sci. 2020, 21, 2876. https://doi.org/10.3390/ijms21082876

AMA Style

Li A-L, Hao Y, Wang W-Y, Liu Q-S, Sun Y, Gu W. Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors. International Journal of Molecular Sciences. 2020; 21(8):2876. https://doi.org/10.3390/ijms21082876

Chicago/Turabian Style

Li, A-Liang, Yun Hao, Wen-Yan Wang, Qing-Song Liu, Yue Sun, and Wen Gu. 2020. "Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors" International Journal of Molecular Sciences 21, no. 8: 2876. https://doi.org/10.3390/ijms21082876

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