QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity

Iněs J. Sousa, Maria José U Ferreira, J. Molnár, Miguel X. Fernandes

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Multidrug resistance (MDR) represents a major limitation for cancer chemotherapy. There are several mechanisms of MDR but the most important is associated with P-glycoprotein (P-gp) overexpression. The development of modulators of P-gp that are able to re-establish drug sensitivity of resistant cells has been considered a promising approach for overcoming MDR. Macrocyclic lathyrane and jatrophane- type diterpenes from Euphorbia species were found to be strong MDR reversing agents. In this study we applied quantitative structure-activity relationship (QSAR) methodology in order to identify the most relevant molecular features of macrocyclic diterpenes with P-gp inhibitory activity and to determine which structural modifications can be performed to improve their activity. Using experimental biological data at two concentrations (4 and 40 lg/ml), we developed a QSAR model for a set of 51 bioactive diterpenic compounds which includes lathyrane and jatrophane-type diterpenes and another model just for jatrophanes. The cross-validation correlation values for all diterpenes QSAR models developed for biological activities at compound concentrations of 4 and 40 lg/ml were 0.758 and 0.729, respectively. Regarding the prediction ability, we get R2pred values of 0.765 and 0.534 for biological activities at compound concentrations of 4 and 40 lg/ml, respectively. Applying the cross-validation test to jatrophanes QSAR models, we obtained 0.680 and 0.787 for biological activities at compound concentrations of 4 and 40 lg/ml concentrations, respectively. For the same concentrations, the obtained R2pred values for jatrophanes models were 0.541 and 0.534, respectively. The obtained models were statistically valid and showed high prediction ability.

Original languageEnglish
Pages (from-to)542-553
Number of pages12
JournalEuropean Journal of Pharmaceutical Sciences
Volume48
Issue number3
DOIs
Publication statusPublished - Feb 14 2013

Fingerprint

Quantitative Structure-Activity Relationship
Diterpenes
P-Glycoprotein
Multiple Drug Resistance
Euphorbia
Biological Models
jatrophane
Drug Therapy
Pharmaceutical Preparations
Neoplasms

Keywords

  • Macrocyclic diterpenes
  • Multidrug resistance
  • Multiple linear regression
  • P-glycoprotein
  • Quantitative structure-activity relationship

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Medicine(all)

Cite this

QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity. / Sousa, Iněs J.; Ferreira, Maria José U; Molnár, J.; Fernandes, Miguel X.

In: European Journal of Pharmaceutical Sciences, Vol. 48, No. 3, 14.02.2013, p. 542-553.

Research output: Contribution to journalArticle

Sousa, Iněs J. ; Ferreira, Maria José U ; Molnár, J. ; Fernandes, Miguel X. / QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity. In: European Journal of Pharmaceutical Sciences. 2013 ; Vol. 48, No. 3. pp. 542-553.
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