A Novel 3-meta-Pyridine-1,2,4-oxadiazole Derivative of Glycyrrhetinic Acid as a Safe and Promising Candidate for Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells

Abstract

Given the pharmacophore properties of the nitrogen-containing moiety in the molecular structure of P-glycoprotein (P-gp) inhibitors, we report the evaluation of the P-gp inhibitory and MDR reversal activities of 2g , a 3- meta -pyridin-1,2,4-oxadiazole derivative of 18β H -glycyrrhetinic acid. Through molecular docking, we have shown that 2g has the potential to directly interact with the transmembrane domain of P-gp with a low free binding energy (−10.2 kcal/mol). Using KB-8-5 human cervical carcinoma cells and RLS40 murine lymphosarcoma cells, both of which exhibit a multidrug-resistant (MDR) phenotype mediated by P-gp activation, we have shown that 2g , at nontoxic concentrations, effectively increased the intracellular accumulation of fluorescent P-gp substrates (rhodamine 123 or doxorubicin (DOX)), leading to a marked sensitization of the model cells to the cytotoxic effect of DOX. Considering the comparable activity of 2g with verapamil, a known P-gp inhibitor, 2g can be considered as a promising candidate for the development of agents capable of overcoming P-gp-mediated MDR in tumor cells.

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library

“…Although TQ has shown great potency, its clinical trials was suspended recently due to obvious side effects reported in the phase III clinical trial of lung cancer. 28 Therefore, lots of P-gp inhibitors 29–70 with new scaffolds are continuously being developed to enhance activity and selectivity. However, in order to truly obtain clinically applicable sensitizers for resistant tumors, the exploration in this field is still ongoing.…”