Analogues of the lignan pinoresinol and their reversal activities on cell multidrug resistance mediated by P-glycoprotein (P-gp)

TOMASIC T.; LANZA P.A.; VERA D.M.A.; KIKKELJ D. ; LAIOLO J.; GONZÁLEZ M.L.; CARPINELLA M.C

Lisboa

Simposio; COST Action CM1407 Challenging organic synthesis inspired by nature-form natural products chemistry to drug discovery; 2017

P-glycoprotein (P-gp) is a multi-specific efflux transporter belonging to ATP-binding cassette (ABC) family, which significantly impacts on the resistance to anticancer drugs. Previous results demonstrated that the lignan pinoresinol was able to reverse resistance to doxorubicin in P-gp overexpressed leukemia cells. This compound also increased the accumulation of drugs inside the cells, showed a low activation of ATP hydrolysis and antagonized verapamil-stimulated ATPase activity. On the other hand, pinoresinol decreased the presence of P-gp in the cell surface [1]. With the aim of finding derivatives with improved activity, pinoresinol was used as a reference compound for a similarity search using ROCS (OpenEye Scientific Software) in the small library of PXR ligands [2,3] and ZINC DrugsNow subset of commercially available compounds. Twenty three compounds were identified as potential candidates to be submitted to molecular docking studies on P-gp. The modelling showed low estimated free energies of binding ranging from -7.07 to -10.89 Kcal/mol for a panel of compounds, with similar values to those obtained with the potent inhibitors used as reference. From the results obtained, seven compounds were obtained and submitted to in vitro screening. The compounds KDS-26 and ZINC44917327 successfully restored sensitivity to doxorubicin and increased the intracellular doxorubicin accumulation in nM range. A detailed description of the results will be presented. The results obtained positioned these compounds as potential leads for effective agents to overcome P-gp-mediated MDR, leading to better outcomes for chemotherapy.