Design and synthesis of 2-phenylnaphthalenoids as inhibitors of DNA topoisomeraseIIα and antitumor agents

• Forty eight 2-phenylnaphthalenoids derivatives were successfully synthesized.
• Six compounds selectively inhibited DNA Topoisomerase reactions in vitro.
• Compound 5 induced cell cycle arrest and apoptosis MDA-MB-231 cell line.
• Compound 5 inhibited MDA-MB-231 xenografts with lower toxicity than VP16.

Forty eight 2-phenylnaphthalenoids were designed and successfully synthesized. Their in vitro cytotoxicities against the proliferations of MDA-MB-231, A549 and HeLa cell lines and inhibitory activities on DNA topoisomerase were evaluated. The quantitative structure–activity relationship (QSAR) studies were established on the basis of cytotoxicity data from MDA-MB-231 cell line. Among these compounds, compound 5 showed potent antiproliferative activity (IC50 = 1 μM) against MDA-MB-231 cells and inhibitory activity on topoisomeraseIIα. Further, in vivo antitumor study with xenograft nude mice indicated that compound 5 inhibited the growth of MDA-MB-231 cells and showed lower toxicity than etoposide (VP16). This work indicates that 2-phenylnaphthalenoids represent a novel type of TopoIIα-inhibitory scaffold for developing new antitumor chemotherapeutic agents.

Compound 5 induced cell-cycle arrest and apoptosis in MDA-MB-231 cells, and inhibited the growth of MDA-MB-231 xenografts.Figure optionsDownload as PowerPoint slide