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

In this study, a series of new indole derivatives of ursolic acid bearing different <i>N</i>-(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...

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Main Authors:	A-Liang Li, Yun Hao, Wen-Yan Wang, Qing-Song Liu, Yue Sun, Wen Gu
Format:	Article
Language:	English
Published:	MDPI AG 2020-04-01
Series:	International Journal of Molecular Sciences
Subjects:	ursolic acid indole derivatives anticancer activity topoisomerase II apoptosis
Online Access:	https://www.mdpi.com/1422-0067/21/8/2876

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spelling	doaj-df50483d66314c8ea6999dfb7f8e72422020-11-25T02:23:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01212876287610.3390/ijms21082876Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II InhibitorsA-Liang Li0Yun Hao1Wen-Yan Wang2Qing-Song Liu3Yue Sun4Wen Gu5Jiangsu 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, ChinaJiangsu 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, ChinaJiangsu 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, ChinaJiangsu 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, ChinaJiangsu 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, ChinaJiangsu 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, ChinaIn this study, a series of new indole derivatives of ursolic acid bearing different <i>N</i>-(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 <b>5f</b> exhibited the most potent activity against SMMC-7721 and HepG2 cells with IC<sub>50</sub> 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 <b>5f</b> can significantly inhibit the activity of Topoisomerase IIα. Further mechanistic studies performed in SMMC-7721 cells revealed that compound <b>5f</b> can elevate the intracellular ROS levels, decrease mitochondrial membrane potential, and finally lead to the apoptosis of SMMC-7721 cells. Collectively, compound <b>5f</b> is a promising Topoisomerase II (Topo II) inhibitor, which exhibited the potential as a lead compound for the discovery of novel anticancer agents.https://www.mdpi.com/1422-0067/21/8/2876ursolic acidindole derivativesanticancer activitytopoisomerase IIapoptosis
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	A-Liang Li Yun Hao Wen-Yan Wang Qing-Song Liu Yue Sun Wen Gu
spellingShingle	A-Liang Li Yun Hao Wen-Yan Wang Qing-Song Liu Yue Sun Wen Gu Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors International Journal of Molecular Sciences ursolic acid indole derivatives anticancer activity topoisomerase II apoptosis
author_facet	A-Liang Li Yun Hao Wen-Yan Wang Qing-Song Liu Yue Sun Wen Gu
author_sort	A-Liang Li
title	Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors
title_short	Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors
title_full	Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors
title_fullStr	Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors
title_full_unstemmed	Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors
title_sort	design, synthesis, and anticancer evaluation of novel indole derivatives of ursolic acid as potential topoisomerase ii inhibitors
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1661-6596 1422-0067
publishDate	2020-04-01
description	In this study, a series of new indole derivatives of ursolic acid bearing different <i>N</i>-(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 <b>5f</b> exhibited the most potent activity against SMMC-7721 and HepG2 cells with IC<sub>50</sub> 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 <b>5f</b> can significantly inhibit the activity of Topoisomerase IIα. Further mechanistic studies performed in SMMC-7721 cells revealed that compound <b>5f</b> can elevate the intracellular ROS levels, decrease mitochondrial membrane potential, and finally lead to the apoptosis of SMMC-7721 cells. Collectively, compound <b>5f</b> is a promising Topoisomerase II (Topo II) inhibitor, which exhibited the potential as a lead compound for the discovery of novel anticancer agents.
topic	ursolic acid indole derivatives anticancer activity topoisomerase II apoptosis
url	https://www.mdpi.com/1422-0067/21/8/2876
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Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors

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