PMID: 22583416May 16, 2012Paper

Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes: structure-activity relationships and pharmacophore modeling

Anti-cancer Agents in Medicinal Chemistry
Mariana ReisMaria-José U Ferreira

Abstract

Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (Pglycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore modeling and structure-activity relationships studies of sixteen macrocyclic diterpenes and polycyclic derivatives obtained from Euphorbia species. The MDR human colon adenocarcinoma cells (COLO 320 MDR) overexpressing P-gp were used as the biological model to screen for P-gp dependent efflux inhibitors. Most of the compounds showed potential as MDR reversal agents. Combined analysis of two different statistic algorithms, K-means clustering and Principal Component Analysis discriminated two clusters and showed a strong correlation between log P and MDR reversal activity for compounds 1-5. The most effective compounds (1-4 and 11-12) were tested in combination with doxorubicin and all potentiated its activity lowering the ID50. Pharmacophore modeling allowed the definition of an aromatic moiety as an additional feature to a previous published P-gp pharmacophore, creating a new five-point pharmacophore with enhanced selectivity for the most active compounds of the present study. Do...Continue Reading

Citations

Aug 1, 2013·Phytochemistry·Sofia A C MendesMaria-José U Ferreira
Jan 23, 2013·Journal of Medicinal Chemistry·Mariana ReisMaria-José U Ferreira
Nov 13, 2015·Journal of Natural Products·Mariana A ReisMaria-José U Ferreira
Apr 23, 2016·Future Medicinal Chemistry·Rafael BaptistaMaria-José U Ferreira
Jul 9, 2016·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Mariana Alves ReisMaria-José U Ferreira
Apr 20, 2017·Journal of Natural Products·Mariana A ReisMaria-José U Ferreira
Aug 4, 2015·Physical Chemistry Chemical Physics : PCCP·Ricardo J FerreiraDaniel J V A dos Santos
Jun 21, 2019·Phytochemical Analysis : PCA·Sara NetoMaria-José U Ferreira
Apr 16, 2020·Phytochemistry Reviews : Proceedings of the Phytochemical Society of Europe·Maryam FattahianIkhlas A Khan
Apr 4, 2017·Phytotherapy Research : PTR·Muhammad Torequl Islam
May 28, 2020·Frontiers in Pharmacology·Mariana Alves ReisMaria-José U Ferreira
Sep 4, 2016·Bioorganic & Medicinal Chemistry·Cátia RamalheteMaria-José U Ferreira
Jun 28, 2013·Journal of Chemical Information and Modeling·Ricardo J FerreiraDaniel J V A dos Santos

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