Artepillin C isoprenomics: design and synthesis of artepillin C isoprene analogues as lipid peroxidation inhibitor having low mitochondrial toxicity

Bioorg Med Chem. 2006 Aug 15;14(16):5721-8. doi: 10.1016/j.bmc.2006.04.015. Epub 2006 May 11.

Abstract

We designed and synthesized isoprene analogues of artepillin C, a major component of Brazilian propolis, and investigated the inhibitory activity on lipid peroxidation of rat liver mitochondria (RLM) and RLM toxicity based on isoprenomics. We succeeded in the synthesis of artepillin C isoprene analogues using regioselective prenylation within the range from 22% to 53% total yield. Reactivity of artepillin C and its isoprene analogues with ABTS (2,2'-Azinobis(3-ethylbenzothiazoline-6-sulfonate)) radical cations showed only a slight difference among the molecules. The isoprene side-chain elongation analogues of artepillin C showed almost the same inhibitory activity against RLM lipid peroxidation as artepillin C. Artepillin C and its isoprene analogues had very weak RLM uncoupling activity. Moreover, artepillin C and its isoprene analogues exhibited a lower inhibitory activity against adenosine 5'-triphosphate (ATP) synthesis by about two orders of magnitude than the effective inhibitory activity against RLM lipid peroxidation. From these results we conclude that artepillin C isoprene analogues could be potent lipid peroxidation inhibitors having low mitochondrial toxicity. We also conclude that elongation of the isoprene side chain of artepillin C to increase lipophilicity had little influence on the inhibitory activity toward RLM lipid peroxidation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Butadienes / chemical synthesis
  • Butadienes / pharmacology*
  • Drug Design
  • Fatty Acids / chemical synthesis
  • Fatty Acids / pharmacology*
  • Hemiterpenes / chemical synthesis
  • Hemiterpenes / pharmacology*
  • Lipid Peroxidation / drug effects*
  • Male
  • Mitochondria, Liver / drug effects*
  • Models, Chemical
  • Pentanes / chemical synthesis
  • Pentanes / pharmacology*
  • Phenylpropionates / chemical synthesis
  • Phenylpropionates / pharmacology*
  • Rats
  • Rats, Wistar

Substances

  • Butadienes
  • Fatty Acids
  • Hemiterpenes
  • Pentanes
  • Phenylpropionates
  • lipid peroxidation inhibitor
  • isoprene
  • artepillin C
  • Adenosine Triphosphate