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. 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.
Keywords: Macrocyclic diterpenes, Jatrophane, Lathyrane, Euphorbia, Euphorbiaceae, Multidrug resistance, P-glycoprotein, Pharmacophore, Docking, Colon Adenocarcinoma
Anti-Cancer Agents in Medicinal Chemistry
Title:Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling
Volume: 12 Issue: 9
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:
Keywords: Macrocyclic diterpenes, Jatrophane, Lathyrane, Euphorbia, Euphorbiaceae, Multidrug resistance, P-glycoprotein, Pharmacophore, Docking, Colon Adenocarcinoma
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. 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.
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Reis Mariana, J. Ferreira Ricardo, Serly Julianna, Duarte Noelia, M. Madureira Ana, J. V. A. Santos Daniel, Molnar Joseph and U. Ferreira Maria-Jose, Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling, Anti-Cancer Agents in Medicinal Chemistry 2012; 12 (9) . https://dx.doi.org/10.2174/187152012803529655
DOI https://dx.doi.org/10.2174/187152012803529655 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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