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

•Three diphyllin glycosides CA, CleA and CleT have been synthesized.•CA and CleT showed anti-proliferative activity at nanomolar concentrations.•CA and CleT showed potent inhibitory effect on V-ATPase.•CA and CleT were identified as novel V-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.

Graphical abstractThree diphyllin glycosides CA, CleA and CleT were synthesized. CA and CleT showed were identified as novel vacuolar H+ ATPase inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide