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

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.