TY - JOUR
T1 - Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes
T2 - Structure-activity relationships and pharmacophore modeling
AU - Reis, Mariana
AU - Ferreira, Ricardo J.
AU - Serly, Julianna
AU - Duarte, Noélia
AU - Madureira, Ana M.
AU - Santos, Daniel J.V.A.
AU - Molnár, Joséph
AU - Ferreira, Maria José U.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Docking
KW - Euphorbia
KW - Euphorbiaceae
KW - Jatrophane
KW - Lathyrane
KW - Macrocyclic diterpenes
KW - Multidrug resistance
KW - P-glycoprotein
KW - Pharmacophore
UR - http://www.scopus.com/inward/record.url?scp=84872231481&partnerID=8YFLogxK
U2 - 10.2174/187152012803529655
DO - 10.2174/187152012803529655
M3 - Article
C2 - 22583416
AN - SCOPUS:84872231481
SN - 1871-5206
VL - 12
SP - 1015
EP - 1024
JO - Anti-Cancer Agents in Medicinal Chemistry
JF - Anti-Cancer Agents in Medicinal Chemistry
IS - 9
ER -