TY - JOUR

T1 - 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

AU - Moralev, Arseny D.

AU - Salomatina, Oksana V.

AU - Chernikov, Ivan V.

AU - Salakhutdinov, Nariman F.

AU - Zenkova, Marina A.

AU - Markov, Andrey V.

N1 - This research was supported by the Russian Science Foundation (Grant No. 23-14-00374) (synthesis, in silico and in vitro studies) and partly by the Russian state-funded budget project of ICBFM SB RAS No. 121031300044-5 (the use of the equipment). © 2023 The Authors. Published by American Chemical Society.

PY - 2023/12/26

Y1 - 2023/12/26

N2 - 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.

AB - 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.

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85180074782&origin=inward&txGid=2f036003b4b12d7028678f38e81a32d6

UR - https://www.mendeley.com/catalogue/0960a253-fd12-3d31-bac8-8d5d077ec718/

U2 - 10.1021/acsomega.3c06202

DO - 10.1021/acsomega.3c06202

M3 - Article

C2 - 38162726

VL - 8

SP - 48813

EP - 48824

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 51

ER -