Fourteen diphyllin 4- C -substituted alkylide derivatives were designed and synthesized using a Heck coupling and subsequent hydrogenation reaction. Olefins 3g and 3i exhibited the highest cytotoxicity on breast cancer cell lines MCF-7 with IC 50 values of 0.08 and 0.07 µM, and they showed weaker V-ATPase inhibitory potency compared to diphyllin.