Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 17, 14 Issues, 2017

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Institut de Chimie de Clermont-Ferrand
Université Clermont Auvergne

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Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling

Anti-Cancer Agents in Medicinal Chemistry, 12(9): 1015-1024.

Author(s): Mariana Reis, Ricardo J. Ferreira, Julianna Serly, Noelia Duarte, Ana M. Madureira, Daniel J. V. A. Santos, Joseph Molnar and Maria-Jose U Ferreira.

Affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003, Lisboa, Portugal.


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. Docking results also show the importance of an aromatic moiety, positively identifying the most relevant residues that can be linked to an inhibitory activity increase.


Macrocyclic diterpenes, Jatrophane, Lathyrane, Euphorbia, Euphorbiaceae, Multidrug resistance, P-glycoprotein, Pharmacophore, Docking, Colon Adenocarcinoma.

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Article Details

Volume: 12
Issue Number: 9
First Page: 1015
Last Page: 1024
Page Count: 10
DOI: 10.2174/187152012803529655
Price: $58

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