Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes

Structure-activity relationships and pharmacophore modeling

Mariana Reis, Ricardo J. Ferreira, Julianna Serly, Noélia Duarte, Ana M. Madureira, Daniel J V A Santos, J. Molnár, Maria José U Ferreira

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1015-1024
Number of pages10
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume12
Issue number9
DOIs
Publication statusPublished - 2012

Fingerprint

Euphorbia
Diterpenes
Multiple Drug Resistance
Structure-Activity Relationship
Colon
Adenocarcinoma
Biological Models
Principal Component Analysis
Doxorubicin
Cluster Analysis
Drug Therapy
Pharmaceutical Preparations
Neoplasms

Keywords

  • Docking
  • Euphorbia
  • Euphorbiaceae
  • Jatrophane
  • Lathyrane
  • Macrocyclic diterpenes
  • Multidrug resistance
  • P-glycoprotein
  • Pharmacophore

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Pharmacology

Cite this

Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes : Structure-activity relationships and pharmacophore modeling. / Reis, Mariana; Ferreira, Ricardo J.; Serly, Julianna; Duarte, Noélia; Madureira, Ana M.; Santos, Daniel J V A; Molnár, J.; Ferreira, Maria José U.

In: Anti-Cancer Agents in Medicinal Chemistry, Vol. 12, No. 9, 2012, p. 1015-1024.

Research output: Contribution to journalArticle

Reis, Mariana ; Ferreira, Ricardo J. ; Serly, Julianna ; Duarte, Noélia ; Madureira, Ana M. ; Santos, Daniel J V A ; Molnár, J. ; Ferreira, Maria José U. / Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes : Structure-activity relationships and pharmacophore modeling. In: Anti-Cancer Agents in Medicinal Chemistry. 2012 ; Vol. 12, No. 9. pp. 1015-1024.
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