Synthesis and identification of cytotoxic diphyllin glycosides as vacuolar H(+)-ATPase inhibitors.

The concise syntheses of two natural diphyllin glycosides Cleistanthin-A (CA), Cleistanthoside-A (CleA) and its derivative, Cleistanthoside-A tetraacetate (CleT), have been achieved. They were evaluated for their in vitro anti-proliferative activities against MCF-7, HeLa, HepG2, HCT-116, U251 cancer cell lines by MTT assay. Both of CA and CleT were anti-proliferative to these cancer cells at nanomolar concentrations. They have been shown to inhibit the activity of vacuolar H(+)-ATPase (V-ATPase) in HepG2 cells and neutralize the pH of lysosomes at nanomolar concentrations.