Synergistic interaction between p-glycoprotein modulators and epirubicine on resistant cancer cells

The macrocyclic lathyrane diterpene latilagascene B, previously isolated from Euphorbia lagascae, was acylated to afford three new diterpene esters, latilagascenes G (1), H (2), and I (3), whose structures were assigned by spectroscopic methods. These acyl derivatives, and the macrocyclic diterpenes of the jatrophane-type, tuckeyanols A (4) and B (5), and euphotuckeyanol (6), isolated from Euphorbia tuckeyana, were tested for P-gp modulating properties on human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines. All the compounds displayed very strong activity. The molecular orbital energies (HOMO and LUMO) of diterpenes 1–6 and 7–13, previously isolated, have also been calculated in order to estimate their probable charge transfer interactions with P-gp. Structure–activity relationships (SAR) are discussed. Furthermore, compounds (1–6) were assayed, in vitro, for their antiproliferative effects in combination with epirubicine and all of them synergistically enhance the effect of the antitumor drug.

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