Abstract
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.
Highlights
Cancer has become a major cause of death in human beings
The close correlations between the topoisomerase II (Topo II) inhibitory activity and cytotoxic activity suggested that Topo II inhibition of the title compounds probably played an important role in their anticancer activity
Tafkuernthteorgientvheesrt,itghaetimonosl.ecular docking results in combination with topoisomerase inhibition assay data indicated that compound 5f could be a promising Topo IIα inhibitor worthy of further investigations
Summary
Cancer has become a major cause of death in human beings. In 2018, there were estimated 18.1 million new cancer cases and 9.6 million cancer deaths worldwide [1]. Most synthesized compounds showed considerable cytotoxic activity against two cancer cell lines. Compounds 4a–c, 4e, 5a, 5e, and 6b–e showed good inhibitory activity to the two cancer cell lines. The results indicated that the anticancer activities of the synthesized compounds were affected by the N-containing moieties anchored on the side chain. Compounds 4a–d, 5a–d, and 6a–d containing NH2, N(Me), N(Et), and piperidine moieties generally showed strong activities. Three dimeric derivatives 7a–c were all inactive to tested cancer cells (IC50 > 50 μM), which indicated that such dimerization by alkyl linkers might hinder the interaction between these compounds and their potential targets, significantly decreasing their anticancer activities
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