Enhancing Macrocyclic Diterpenes as Multidrug-Resistance Reversers: Structure鈥揂ctivity Studies on Jolkinol D Derivatives
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- 作者：Mariana Reis ; Ricardo J. Ferreira ; Maria M. M. Santos ; Daniel J. V. A. dos Santos ; Joseph Moln谩r ; Maria-Jos茅 U. Ferreira
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：56
- 期：3
- 页码：748-760
- 全文大小：479K
- 年卷期：v.56,no.3(February 14, 2013)
- ISSN：1520-4804
文摘
The phytochemical study of Euphorbia piscatoria yielded jolkinol D (<b>1b>) in a large amount, whose derivatization gave rise to 12 ester derivatives (<b>2b>鈥?b>13b>) and hydrolysis to compound <b>14b>. The in vitro modulation of P-gp of compounds <b>1b>鈥?b>14b> 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 (<b>2b>鈥?b>14b>) showed potential as MDR reversal agents. In this small library of novel bioactive macrocyclic lathyrane diterpene derivatives, designed to evaluate structure鈥揳ctivity 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.