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

• Published in: European journal of medicinal chemistry 2022-12, Vol.243, p.114706-114706, Article 114706
• Main Authors: Xu, Guangsen, Li, Zhiying, Ding, Yanjiao, Shen, Yuemao
• Format: Article
• Language: English
• Subjects: Antitumor; Catalytic inhibitor; Human DNA topoisomerase IIα
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114706

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. [Display omitted] •Fifty eight new 1,2-diphenylethene derivatives were synthesized as DNA TopoIIα inhibitors.•Amongst, F2 showed better bioactivity and selectivity than that of VP-16.•F2 is a non-intercalative ATP-competitive human DNA topoisomerase IIα catalytic inhibitor.•F2 showed a better safety in vivo than that of VP-16.