Enhancing Macrocyclic Diterpenes as Multidrug-Resistance Reversers: Structure–Activity Studies on Jolkinol D Derivatives

The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to 12 ester derivatives (2–13) and hydrolysis to compound 14. The in vitro modulation of P-gp of compounds 1–14 was evaluated through a combination of transport and chemosensitivity assays, using the L5178 mouse T lymphoma cell line transfected with the human MDR1 gene. Apart from jolkinol D, all derivatives (2–14) showed potential as MDR reversal agents. In this small library of novel bioactive macrocyclic lathyrane diterpene derivatives, designed to evaluate structure–activity relationships essential in overcoming multidrug resistance (MDR), some correlations between MDR reversal and molecular weight, accessible solvent areas, and octanol/water partition coefficient were identified that can contribute to the development of new selective P-gp reversal agents.This study was supported by FCT (Fundação para a Ciência e a ̂Tecnologia, Portugal) by Research Projects PTDC/QUI-QUI/099815/2008 and PEst-OE/SAU/UI4013/2011. M.R. acknowledges FCT for her Ph.D. Grant SFRH/BD/72915/2010. The authors thank Dr. Teresa Vasconcelos, Instituto Superior de Agronomia, Universidade de Lisboa, Portugal, for the taxonomic work on the plant material