First Total Synthesis of Protoapigenone and Its Analogues as Potent Cytotoxic Agents

Protoapigenone (1), isolated from Thelypteris torresiana, previously showed significant cytotoxic activity against five human cancer cell lines. In a continued structure−activity relationship study, the first total synthesis and modification of 1 were achieved. All synthesized compounds and related intermediates were evaluated for cytotoxic activity against five human cancer cell lines, HepG2, Hep3B, MDA-MB-231, MCF-7, and A549. Among them, 24 showed 2.2−14.2-fold greater cytotoxicity than 1 and naphthyl A-ring analogues remarkably enhanced the activity.