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

Eur J Med Chem. 2014 Jul 23:82:466-71. doi: 10.1016/j.ejmech.2014.06.002. Epub 2014 Jun 3.

Abstract

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.

Keywords: Cleistanthin-A; Cleistanthoside-A; Inhibitor; Synthesis; Vacuolar H(+)-ATPase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disaccharides / chemical synthesis
  • Disaccharides / chemistry
  • Disaccharides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycosides / chemical synthesis
  • Glycosides / chemistry
  • Glycosides / pharmacology*
  • HCT116 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Lignans / chemical synthesis
  • Lignans / chemistry
  • Lignans / pharmacology*
  • Lysosomes / drug effects
  • MCF-7 Cells
  • Molecular Conformation
  • Structure-Activity Relationship
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • Antineoplastic Agents
  • Benzofurans
  • Disaccharides
  • Enzyme Inhibitors
  • Glycosides
  • Lignans
  • cleistanthoside A tetraacetate
  • cleistanthin
  • Vacuolar Proton-Translocating ATPases