Synthesis of 2‐phenylnaphthalenoid amide derivatives and their topoisomerase IIα inhibitory and antiproliferative activities

Abstract

AbstractTopoisomerases are highly associated with cell proliferation, becoming an important target for the development of antitumor drugs. 2‐Phenylnaphthalenoids (2PNs) have been identified as human DNA topoisomerase IIα (TopoIIα) inhibitors. In this study, based on the 2PN scaffold, 20 amide derivatives (J1–J10, K1–K10) were synthesized. Among them, K10 showed high TopoIIα inhibitory activity and stronger antiproliferation activity against HepG‐2 and MDA‐MB‐231 cells (IC50 0.33 and 0.63 μM, respectively) than the positive control VP‐16 (IC50 9.19 and 10.86 μM) and the lead F2 (IC50 0.64 and 1.51 μM). Meanwhile, K10 could also inhibit migration and promote apoptosis of HepG‐2 and MDA‐MB‐231 cells. Therefore, K10 can be developed into a potent TopoIIα inhibitor as an antitumor agent. The structure–activity relationship was also discussed.