Helenanolide type sesquiterpene lactones. Part 5: The role of glutathione addition under physiological conditions

Sesquiterpene lactones (STLs) are known to exert most of their numerous bio logical activities through inhibition of enzymes and other functional prote ins by forming covalent bonds with free cysteine residues in these macromol ecules. The question arises how these drugs can alkylate such vital target structures instead of being quickly deactivated by reaction with the cystei ne group of glutathione (GSH) which is present in high concentrations in al l cells. We have measured in this study the pH dependent kinetics of GSH ad dition to the cyclopentenone and alpha-methylene-gamma-lactone group of hel enanolide type sesquiterpene lactones using UV-spectrophotometry. The react ion with GSH at physiological pH proceeds very quickly but is reversible so that a fraction of STL molecules-will always be available for reaction wit h protein targets. In agreement with these chemical data, helenalin-monoand -bis-glutathionyl adducts were demonstrated to inhibit the nuclear transcr iption factor NF-kappa B at concentrations similar to the free sesquiterpen e lactone. (C) 1999 Elsevier Science Ltd. All rights reserved.