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The cytotoxic effects of terpenoid lactones are attributed to the alkylation of biological nucleophiles, especially sulfhydryl groups in proteins, by the α,β-unsaturated carbonyl moiety of lactones through Michael reaction. Therefore, the cytotoxicity could be reflected by the reactivity of the pharmacophores. In this work, the Michael reaction between 12 α,β-unsaturated-carbonyl-containing small species, i.e. 10 analogues of the alpha methylene gamma butyrolactone moiety of andrographolide, one cyclopentenone, and one methylene–pentanolide, and L-cysteine-methylester-1 were investigated by ab initio methods to mimic the alkylation of proteins by terpenoid lactones. The trend in the calculated reaction free energies of the small species is qualitatively in accordance with the reported cytotoxicity of corresponding terpenoid lactones. [ABSTRACT FROM AUTHOR]

The cytotoxic effects of terpenoid lactones are attributed to the alkylation of biological nucleophiles, especially sulfhydryl groups in proteins, by the α,β-unsaturated carbonyl moiety of lactones through Michael reaction. Therefore, the cytotoxicity could be reflected by the reactivity of the pharmacophores. In this work, the Michael reaction between 12 α,β-unsaturated-carbonyl-containing small species, i.e. 10 analogues of the alpha methylene gamma butyrolactone moiety of andrographolide, one cyclopentenone, and one methylene–pentanolide, and L-cysteine-methylester-1 were investigated by ab initio methods to mimic the alkylation of proteins by terpenoid lactones. The trend in the calculated reaction free energies of the small species is qualitatively in accordance with the reported cytotoxicity of corresponding terpenoid lactones. [ABSTRACT FROM AUTHOR]