Background: Diphyllin, an arylnaphthalene lignan lactone, isolated from many traditional medicinal plants, has
been reported to possess anticancer and antiviral activities. Natural diphyllin and its glycosides were identified as potent
-ATPase (V-ATPase) inhibitors.
Objective: The aim of this study was to design and synthesize a series of heterocyclic derivatives of diphyllin as novel
Methods: The targeted heterocyclic derivatives of diphyllin were synthesized from diphyllin employing etherification
reaction and N-substitution reaction. Cytotoxicity of these compounds on four cancer cells was assessed by MTT assay. The
inhibitory activity of V-ATPase of compound 3n was measured on MGC-803 cells. Anti-migration and anti-invasion
abilities were assessed by transwell invasion assay and scratch wound assay.
Results: Most of these derivatives displayed potent cytotoxicity on four cancer cells at submicromolar concentrations. The
most potent derivative 3n has been shown to inhibited V-ATPase activity, migration and invasion abilities on MGC-803
cells at 0.75 mM.
Conclusion: The collective results clearly indicate that heterocyclic derivatives of diphyllin inhibit the viability, V-ATPase
activity, migration and invasion of the MGC803 cells. The current findings provide valuable insights for the future
development of novel diphyllin derivatives as anticancer agents.