Synthesis and Evaluation of Cleistanthin A Derivatives as Potent Vacuolar H(+) -ATPase Inhibitors.

Twelve new glycosides and alkane derivatives of cleistanthin A were designed and synthesized. Their in vitro antiproliferative activity was investigated against HCT-116, HepG2, A549, Hela tumor cell lines and HEK293 cell by MTT assay. Most of these compounds displayed antiproliferative effects on four cancer cells at submicromolar concentration, but they were less potent than cleistanthin A Moreover, they showed no antiproliferative effects on HEK293 cell at 200 nm. The most potent compounds, 3e and 4a, have been shown to inhibit the activity of vacuolar H(+) -ATPase (V-ATPase) and neutralize the pH of lysosomes at submicromolar concentrations.