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

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 β-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 2β,13(11β)-bis-glutathionyl adduct. In contrast, addition of free cys highly favoured the exocyclic methylene group. Addition of GSH to the cyclopentenone of 11α,13-dihydrohelenalin (plenolin) showed the same characteristics as observed with helenalin while 2α-acetoxy-2,3-dihydro-4β 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.