Synthesis and evaluation of cytotoxic and Na+/K+-ATP-ase inhibitory activity of selected 5α-oleandrigenin derivatives

Eur J Med Chem. 2019 Oct 15:180:417-429. doi: 10.1016/j.ejmech.2019.07.028. Epub 2019 Jul 9.

Abstract

Oleandrin, the major biologically active constituent of shrub Nerium oleander preparations of which have been used in traditional Mediterranean and Asian medicine, attracts a great deal of attention due to its pronounced anticancer activity. The synthesis of oleandrigenin model, 16β-hydroxy-3β-methoxy-5α-card-20(22)-enolide 16-acetate, from androstenolone acetate through 17β-(3-furyl)-intermediates has been developed. Several related 17β-(butenolidyl)- and 17β-(furyl)-androstane derivatives were synthesized and tested for in vitro cytotoxic and Na+/K+-ATP-ase inhibitory activities. Comparison of Na+/K+-ATP-ase inhibitory and cytotoxic activity underlines complex nature of the relationship.

Keywords: ATP-ase inhibition; Cardenolides; Cytotoxicity; Furan transformation; Partial synthesis.

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cardenolides / chemical synthesis
  • Cardenolides / chemistry
  • Cardenolides / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Conformation
  • Nerium / chemistry
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents, Phytogenic
  • Cardenolides
  • Enzyme Inhibitors
  • oleandrigenin
  • Sodium-Potassium-Exchanging ATPase