Study of the reversal of multidrug resistance by compounds obtained from native and naturalized plants of central Argentina: binding mode of pinoresinol to P-glycoprotein.

CARPINELLA M. C.; GONZÁLEZ M. L.; VERA M.; JORAY M.B.; MACCIONI M.; PALACIOS S.; RUMJANEK V.

Budapest

Conferencia; Meet the Experts 2014 Conference; 2014

Fifteen compounds with different bioactivities previously obtained in the laboratory from native and naturalized plants of central Argentina were tested for their capacity of reversing P-gp mediated chemotherapeutic efflux in the MDR derivative of K562 cells, Lucena 1. After performing MTT assay and the measurement of doxorubicin (DOX) intracellular accumulation by flow cytometry, the compounds (±)pinoresinol (1) (Fig. 1), obtained from the ethanolic extract of Melia azedarach 1, and dalenin (2) (Fig.1), a novel molecule isolated from Dalea elegans 2, were the most active, being the first the most potent. At 40 mg/ml, 1 decreased 9.4 times the IC50 of DOX in Lucena 1 cells and enhanced the uptake of the cytotoxic, reaching those values observed in K562. Compound 1 showed the same level of effectiveness as verapamil, used as reference drug. Docking studies showed that pinoresinol binds to different aromatic residues participating in the "v" vortex involving the trans-membrane a-helices 4, 5 and 6, in the same region where powerful known inhibitors, such as tariquidar, were found to bind to 3. The results suggest that compound 1 has great potential to be further developed as a P-gp inhibitor.