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

摘要

Forty eight 2-phenylnaphthalenoids were designed and successfully synthesized. Their in vitro cyto-toxicities 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 (IC_(50) = 1 muM) against MDA-MB-231 cells and inhibitory activity on topoisomerasella. 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 TopoIIa-inhibitory scaffold for developing new antitumor chemotherapeutic agents.