Structure-Activity Relationships of Cytotoxic Lactones as Inhibitors and Mechanisms of Action.

BACKGROUND: Some lactones prevent protein Myb-dependent gene expression.

OBJECTIVE: The object is to calculate inhibitors of Myb-brought genetic manifestation.

METHOD: Linear quantitative structure-potency relations result expanded, among sesquiterpene lactones of a huge macrocycle variety (pseudoguaianolides, guaianolides, eudesmanolides and germacranolides), to establish which part of the molecules constitutes their pharmacophore, and predict their inhibitory potency on Myb-reliant genetic manifestation, which may result helpful as leads for antileukaemia therapies with a new mechanism of action.

RESULTS: Several count indices are connected with structure-activity. α-Methylene-γ lactone ML functional groups increase whereas OH groups decrease activity. Hydrophobicity provides to increase cell toxicity. Four counts (ML, number of α,β unsaturated CO groups, etc.), connected with the number of oxygens, present a positive association, owing to the negative charge of oxygen. The s trans s trans germacranolide molecule presents maximal potency. Groups OH decrease the potency owing to the positive charge of hydrogen. The numbers of π-systems and atoms, and polarizability increase the potency. Following least squares, every standard error of the regression coefficients are satisfactory in every expression. According to leave-group-out cross-validation, the most predictive linear expressions for lactones, pseudoguaianolides and germacranolides result. Quadratic equations do not better the correlation.

CONCLUSION: Likely action mechanisms for lactones are argued with a diversity of functional groups in the lactone annulus, including artemisinin with its uncommon macrocycle characteristic, 1,2,4 trioxane cycle (pharmacophoric peroxide linkage -O1-O2- in endoperoxide ring), which results the foundation for its sole antimalarial potency.