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 vacuolar H+-ATPase (V-ATPase) inhibitors.
Objective: The aim of this study was to design and synthesize a series of heterocyclic derivatives of
diphyllin as novel anticancer agents.
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 inhibit V-ATPase activity, migration
and invasion abilities on MGC-803 cells at 0.75 μM.
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