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

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 Научная публикация

Журнал

ACS Omega
, E-ISSN: 2470-1343

Вых. Данные

Год: 2023, Страницы: 48813 - 48824 Страниц : 12 DOI: 10.1021/acsomega.3c06202

Ключевые слова

Cells,Drug resistance,Hydrocarbons,Inhibitors,Peptides and proteins

Авторы

Moralev Arseny D. ^1,2 , Salomatina Oksana V. ^1,3 , Chernikov Andrey V. ¹ , Salakhutdinov Nariman F. ³ , Zenkova Marina A. ¹ , Markov Andrey V. ¹

Организации

1	Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences
2	Faculty of Natural Sciences, Novosibirsk State University
3	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry Siberian Branch of the Russian Academy of Sciences

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

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

Поступила в редакцию:	21 авг. 2023 г.
Принята к публикации:	4 дек. 2023 г.
Опубликована в печати:	6 дек. 2023 г.
Опубликована online:	12 дек. 2023 г.

Web of science	WOS:001132953700001
РИНЦ	64740851
OpenAlex	W4389611491