Nitrogen-containing naringenin derivatives for reversing multidrug resistance in cancer

Ricardo J. Ferreira, Márió Gajdács, Annamária Kincses, Gabriella Spengler, Daniel J.V.A. dos Santos, Maria José U. Ferreira

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Article number115798
JournalBioorganic and Medicinal Chemistry
Volume28
Issue number23
DOIs
Publication statusPublished - 1 Dec 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Ltd

Keywords

  • Docking
  • Efflux modulators
  • Flavonoids
  • Molecular dynamics
  • Multidrug resistance
  • P-glycoprotein

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