Enhancing macrocyclic diterpenes as multidrug-resistance reversers: Structure-activity studies on jolkinol D derivatives

Mariana Reis, Ricardo J. Ferreira, Maria M.M. Santos, Daniel J.V.A. Dos Santos, Joseph Molnár, Maria José U. Ferreira

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)748-760
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
DOIs
Publication statusPublished - 14 Feb 2013
Externally publishedYes

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