Planta Med 2012; 78 - PD36
DOI: 10.1055/s-0032-1320394

Structure activity-relationships of P-Glycoprotein modulation using a small library of macrocyclic lathyrane diterpenes

M Reis 1, RJ Ferreira 1, MMM Santos 1, DJVA dos Santos 1, J Molnár 2, MJU Ferreira 1
  • 1Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisboa, Portugal
  • 2Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary

Multidrug resistance is a major hurdle for the success of cancer chemotherapy. The main cause for this phenomenon is attributed to the overexpression of the efflux pump, P-glycoprotein (P-gp). A small library of novel bioactive macrocyclic lathyrane-type diterpene derivatives was developed to discover a selective P-gp reversal agent. In this way, a macrocyclic diterpene was acylated with different alkanoyl and aroyl anhydrides/chlorides. In order to explore the role of the substitution pattern on the modulation of P-gp efflux, the anti-MDR effects of compounds were evaluated in human MDR1-gene transfected mouse lymphoma cells, through the rhodamine-123 exclusion assay.

Furthermore, some of the compounds synergistically enhanced the antiproliferative effect of doxorubicin. The combination of these results with physicochemical descriptors allowed inferring some structure-activity relationships. Strong correlations were found between activity and molecular weight, accessible solvent areas or octanol/water partition coefficient.

Acknowledgements: This study was supported by FCT, Portugal (project PTDC/QUI-QUI/099815/2008; PhD grant SFRH/BD/72915/2010; PEst-OE/SAU/UI4013/2011).