TY - JOUR
T1 - Nitrogen-containing naringenin derivatives for reversing multidrug resistance in cancer
AU - Ferreira, Ricardo J.
AU - Gajdács, Márió
AU - Kincses, Annamária
AU - Spengler, Gabriella
AU - dos Santos, Daniel J.V.A.
AU - Ferreira, Maria José U.
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Docking
KW - Efflux modulators
KW - Flavonoids
KW - Molecular dynamics
KW - Multidrug resistance
KW - P-glycoprotein
UR - http://www.scopus.com/inward/record.url?scp=85092096903&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2020.115798
DO - 10.1016/j.bmc.2020.115798
M3 - Article
C2 - 33038666
AN - SCOPUS:85092096903
SN - 0968-0896
VL - 28
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 23
M1 - 115798
ER -