Synthesis and evaluation of diphyllin β-hydroxyl amino derivatives as novel V-ATPase inhibitors

Abstract

Natural diphyllin glycosides were identified as potent vacuolar H⁺ -ATPase (V-ATPase) inhibitors. A series of diphyllin β-hydroxyl amino derivatives were designed and synthesized as novel diphyllin derivatives. Most of these derivatives displayed potent cytotoxicity against six cancer cell lines with IC₅₀ values in the submicromolar to nanomolar concentration range. Compounds 2b, 2c, 2l, 2m, and 2n showed similar V-ATPase inhibitory potency to Bafilomycin A1. Compound 2l exhibited potent activity of modulation of lysosomal pH and cytoplasmic pH.

Keywords: V-ATPase inhibitor; cytotoxicity; diphyllin; synthesis; β-hydroxyl amino derivatives.