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 (213) and hydrolysis to compound 14. The in vitro modulation of P-gp of compounds 114 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 (214) 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.

Mariana Reis, Ricardo J. Ferreira, Maria M. M. Santos, Daniel J. V. A. dos Santos, Joseph Molnár, and Maria-José U. Ferreira*

Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-019, Lisboa, Portugal
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary

http://dx.doi.org/10.1021/jm301441w

 

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