期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 127, 期 -, 页码 586-598出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.01.019
关键词
MDR reversers; P-gp modulators; N-alkanol-N-cyclohexanol amine aryl esters; Chemosensitizers; Doxorubicin-resistant human; erythroleukemia K562 cells (K562/DOX); Pirarubicin uptake
资金
- MIUR [FIRB 2012 RBFR12S0Q1_003]
- University of Florence
In a continuing search for potent P-gp-dependent multidrug-resistant (MDR) reversers we synthesized and studied a new series of N-alkanol-N-cyclohexanol amine aryl esters characterized by the presence of two linkers with different flexibility: a polymethylene chain of variable length and a cyclohexylic scaffold, that gave origin to two geometrical isomers (cis and trans). The reversal activity of the new compounds was evaluated on the K562/DOX cell line by three tests: pirarubicin uptake modulation, doxorubicin cytotoxicity enhancement (reversal fold, RF) and inhibition of P-gp-mediated rhodamine123 (Rhd 123) efflux tests. The chemical stability of their ester function was evaluated in the experimental conditions utilized (phosphate buffer solution (PBS), bovine serum and in the presence of K562/ DOX cells) and in human plasma. The new series of molecules showed very interesting MDR reversing properties; in particular compound 5b (ELF26B), characterized by trans stereochemistry and a 5 methylene chain, presented the best pharmacological profile and is stable in each tested medium. Compound 5b could be an interesting lead for the development of new potent and efficacious P-gpdependent MDR modulators. (C) 2017 Elsevier Masson SAS. All rights reserved.
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