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 18βH-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

Cite: Moralev A.D. , Salomatina O.V. , Chernikov A.V. , Salakhutdinov N.F. , Zenkova M.A. , Markov A.V.
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
ACS Omega. 2023. P.48813 - 48824. DOI: 10.1021/acsomega.3c06202 WOS РИНЦ

Dates:

Submitted:	Aug 21, 2023
Accepted:	Dec 4, 2023
Published print:	Dec 6, 2023
Published online:	Dec 12, 2023

Identifiers:

Web of science	WOS:001132953700001
Elibrary	64740851
OpenAlex	W4389611491

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