1. Academic Validation
  2. Discovery of 1,2-diphenylethene derivatives as human DNA topoisomerase II catalytic inhibitors and antitumor agents

Discovery of 1,2-diphenylethene derivatives as human DNA topoisomerase II catalytic inhibitors and antitumor agents

  • Eur J Med Chem. 2022 Aug 26;243:114706. doi: 10.1016/j.ejmech.2022.114706.
Guangsen Xu 1 Zhiying Li 1 Yanjiao Ding 1 Yuemao Shen 2
Affiliations

Affiliations

  • 1 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
  • 2 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong, 250012, PR China. Electronic address: yshen@sdu.edu.cn.
Abstract

Human DNA Topoisomerase II (TopoII) is highly correlated with cell proliferation, and involved in tumor biogenesis and development. The classic chemotherapeutic agents etoposide (VP-16) and adriamycin (ADR) targeting TopoII are wildly used in clinical applications. Herein, fifty-eight pinosylvin (1,2-diphenylethene) derivatives as TopoII inhibitors were designed and synthesized through three generations of structural optimizations on the basis of the structure of the initial hit A1 from in-house chemical library. The most potent compound F2 showed high in vitro inhibitory efficacy against TopoII (IC50 α 3.8, β 10.1 μM), compared to that of VP-16 (IC50 α 110.0, β 36.1 μM) for pBR322 DNA relaxation with no evident TopoII poisons in DNA cleavage assay. Meanwhile, F2 exhibited strong antitumor activities against human Cancer cell lines HeLa, HCT-116, PC-3, MDA-MB-231, HepG2 and A549 (IC50 0.1-0.3 μM), compared to that of VP-16 (IC50 1.5-15.1 μM). F2 showed less cytotoxicity against normal murine cell line CCL-226 (IC50 > 50 μM) than that of VP-16 (IC50 20.8 μM). The selectivity index of F2 and VP-16 are larger than 52.1 and 1.3-26.2 in cell lines, respectively. Additionally, F2 exhibited potent potency in Apoptosis induction and cell cycle arrest in HepG2 cells. These results provide a promising strategy and good starting point for the development of potent TopoII inhibitors as antitumor agents.

Keywords

Antitumor; Catalytic inhibitor; Human DNA topoisomerase IIα.

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