2, 4, 5-Trideoxyhexopyranosides derivatives of diphyllin: Synthesis and anticancer activity

Diphyllin and its natural derivatives were identified as potent vacuolar H⁺ -ATPase (V-ATPase) inhibitors. In this study, twelve 2, 4, 5-trideoxyhexopyranosides derivatives of diphyllin were synthesized. Most of these compounds showed potent abilities to inhibit the growth of HT-29, MCF-7, HepG2 cancer cells with IC₅₀ values at submicromolar concentration. The compounds 5c3 and 5c4 showed the best inhibitory activity on breast cancer cell lines MCF-7 with IC₅₀ values of 0.09 and 0.10 μM. Compounds 5c3 and 5c4 showed similar V-ATPase inhibitory potency to diphyllin. Molecular docking showed that a hydrogen bond was found between the hydroxyl of 5c3 and SerA534 in the pocket of the V-ATPase receptor.