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 biological activities through inhibition of enzymes and other functional proteins by forming covalent bonds with free cysteine residues in these macromolecules. The question arises how these drugs can alkylate such vital target structures instead of being quickly deactivated by reaction with the cysteine group of glutathione (GSH) which is present in high concentrations in all cells. We have measured in this study the pH dependent kinetics of GSH addition to the cyclopentenone and alpha-methylene-gamma-lactone group of helenanolide type sesquiterpene lactones using UV-spectrophotometry. The reaction with GSH at physiological pH proceeds very quickly but is reversible so that a fraction of STL molecules will always be available for reaction with protein targets. In agreement with these chemical data, helenalin-mono- and -bis-glutathionyl adducts were demonstrated to inhibit the nuclear transcription factor NF-kappaB at concentrations similar to the free sesquiterpene lactone.