Nitrogen-containing naringenin derivatives for reversing multidrug resistance in cancer.
Basic Information
ID: ALA5244266
Journal: Bioorg Med Chem
Title: Nitrogen-containing naringenin derivatives for reversing multidrug resistance in cancer.
Authors: Ferreira RJ, Gajdács M, Kincses A, Spengler G, Dos Santos DJVA, Ferreira MU.
Abstract: Naringenin (1), isolated from Euphorbia pedroi, was previously derivatized yielding compounds 2-13. In this study, aiming at expanding the pool of analogues of the flavanone core towards better multidrug resistance (MDR) reversal agents, alkylation reactions and chemical modification of the carbonyl moiety was performed (15-39). Compounds structures were assigned mainly by 1D and 2D NMR experiments. Compounds 1-39 were assessed as MDR reversers, in human ABCB1-transfected mouse T-lymphoma cells, overexpressing P-glycoprotein (P-gp). The results revealed that O-methylation at C-7, together with the introduction of nitrogen atoms and aromatic moieties at C-4 or C-4', significantly improved the activity, being compounds 27 and 37 the strongest P-gp modulators and much more active than verapamil. In combination assays, synergistic interactions of selected compounds with doxorubicin substantiated the results. While molecular docking suggested that flavanone derivatives act as competitive modulators, molecular dynamics showed that dimethylation promotes binding to a modulator-binding site. Moreover, flavanones may also interact with a vicinal ATP-binding site in both nucleotide-binding domains, hypothesizing an allosteric mode of action.
CiteXplore: 33038666
DOI: 10.1016/j.bmc.2020.115798
Patent ID: ┄