Synthesis and biological evaluation of Complex I inhibitor R419 and its derivatives as anticancer agents in HepG2 cells

Bioorg Med Chem Lett. 2018 Sep 15;28(17):2957-2960. doi: 10.1016/j.bmcl.2018.07.006. Epub 2018 Jul 6.

Abstract

In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50 = 5.2 ± 0.9 μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50 = 2.8 ± 0.4 μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I.

Keywords: Complex I; Flavonoids derivatives; Human hepatocellular carcinoma; R419.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Electron Transport Complex I / antagonists & inhibitors*
  • Electron Transport Complex I / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hep G2 Cells
  • Humans
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Piperidines
  • R419 compound
  • Electron Transport Complex I