Lathyrol Diterpenes as Modulators of P-Glycoprotein Dependent Multidrug Resistance: Structure-Activity Relationship Studies on Euphorbia factor L3 Derivatives.

Journal of medicinal chemistry

PubMedID: 25856545

Jiao W, Wan Z, Chen S, Lu R, Chen X, Fang D, Wang J, Pu S, Huang X, Gao H, Shao H. Lathyrol Diterpenes as Modulators of P-Glycoprotein Dependent Multidrug Resistance: Structure-Activity Relationship Studies on Euphorbia factor L3 Derivatives. J Med Chem. 2015;.
Five series of 37 new acylate and epoxide derivatives (3-39) of Euphorbia factor L3, a lathyrol diterpene isolated from Euphorbia lathyris, were designed by modifying the hydroxyl moiety of C-3, C-5 or C-15. Chemoreversal effects of the acylates on multidrug resistance (MDR) were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein (P-gp). Eight derivatives exhibited greater chemoreversal ability than verapamil (VRP) against adriamycin (ADR) resistance. Compounds 19 and 25 exhibited 4. 8 and 4. 0 times, respectively, more effective reversal ability than VRP against ADR resistance. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to MDR reversal, we conducted a structure-activity relationship study of these compounds. The simulation studies indicated different possible mechanisms and revealed the important influence of hydrophobic interactions and hydrogen bonds in the flexible cavity of P-gp.