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

[ Vol. 17 , Issue. 2 ]


Francisco Torrens* and Gloria Castellano*   Pages 166 - 182 ( 17 )


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

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

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

Results: Several count indices are connected with structure–activity. The α-methylene-γ-lactone ML functional groups increase, whereas OH groups decrease the 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 partial negative charge of oxygen. The s-trans-strans- germacranolide molecule presents maximal potency. The OH groups 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 coefficients is satisfactory in every expression. The most predictive linear expressions for lactones, pseudoguaianolides and germacranolides are corroborated by leave-group-out cross-validation. Quadratic equations do not make the correlation better.

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 in the foundation for its sole antimalarial potency.


SAR, pharmacophore, bioactiphore, cytotoxic activity, selectivity index, cell viability, Sesquiterpene Lactones (STLs)


Institut Universitari de Ciència Molecular, Universitat de València, Edifici d’Instituts de Paterna, P. O. Box 22085, E-46071 València, Departamento de Ciencias Experimentales y Matemáticas, Facultad de Veterinaria y Ciencias Experimentales, Universidad Católica de Valencia San Vicente Mártir, Guillem de Castro-94, E-46001 València

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