Helenanolide-type sesquiterpene lactones--III. Rates and stereochemistry in the reaction of helenalin and related helenanolides with sulfhydryl containing biomolecules

Bioorg Med Chem. 1997 Apr;5(4):645-53. doi: 10.1016/s0968-0896(97)00003-5.

Abstract

The reactivity of the two potential Michael addition sites of the helenanolide-type sesquiterpene lactone helenalin towards the physiological thiols glutathione (GSH) and cysteine (cys) in aqueous solution was investigated by 1H NMR spectroscopic experiments. In the presence of one molar equivalent of GSH, the reaction was shown to occur with high regio- and stereoselectivity at the beta-position of C-2 in the cyclopentenone ring. Addition to the exocyclic methylene group at the lactone ring was found to occur in the presence, of GSH in molar ratios over 1:1, but proceeded at a rate 10 times smaller than at C-2 leading to the 2 beta,13(11 beta)-bis-glutathionyl adduct. In contrast, addition of free cys highly favoured the exocyclic methylene group. Addition of GSH to the cyclopentenone of 11 alpha, 13-dihydrohelenalin (plenolin) showed the same characteristics as observed with helenalin while 2 alpha-acetoxy-2,3-dihydro-4 beta H-helenalin (chamissonolide) did not form an adduct when incubated with an equimolar amount of GSH. Explanations for the observed differences in reactivity of the two potential reaction sites based on MO computations are given and implications for the biological activity of this type of sesquiterpene lactones are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry*
  • Antineoplastic Agents, Phytogenic / metabolism
  • Binding, Competitive
  • Cysteine / chemistry
  • Cysteine / metabolism*
  • Glutathione / chemistry
  • Glutathione / metabolism*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Sesquiterpenes / chemistry*
  • Sesquiterpenes / metabolism
  • Sesquiterpenes, Guaiane
  • Stereoisomerism
  • Structure-Activity Relationship
  • Toxins, Biological / chemistry*
  • Toxins, Biological / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Sesquiterpenes
  • Sesquiterpenes, Guaiane
  • Toxins, Biological
  • chamissonolide
  • plenolin
  • helenalin
  • Glutathione
  • Cysteine