Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling
2012
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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