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Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter

Bruno M F Gonçalves1, David S P Cardoso1, Maria-José U Ferreira1

  • 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.

Molecules (Basel, Switzerland)
|July 30, 2020
PubMed

Insights

Semisynthetic nitrogen-containing flavonoids and terpenoids show promise in reversing multidrug resistance (MDR) by modulating ATP-binding cassette (ABC) transporters like P-glycoprotein (P-gp). These compounds offer a potential strategy to improve chemotherapy effectiveness.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Natural Products

Background:

  • Multidrug resistance (MDR) significantly limits chemotherapy efficacy in cancer treatment.
  • Overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 1 (MRP1), is a primary mechanism driving MDR.
  • Natural product-derived compounds, particularly flavonoids and terpenoids, are explored for their potential to modulate these efflux pumps.

Purpose of the Study:

  • To review the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as modulators of ABC transporters.
  • To highlight the role of nitrogen-bearing moieties in influencing the modulation of ABC transporter efflux function.
  • To discuss the development of effective MDR reversers based on these modified natural products.

Main Methods:

  • Review of recent literature on semisynthetic modifications of flavonoids and terpenoids.
  • Focus on the introduction of nitrogen-containing functional groups (aliphatic, aromatic, heterocyclic amines, amides).
  • Analysis of the reported inhibitory activities of these derivatives against P-gp, MRP1, and BCRP.

Main Results:

  • Nitrogen-containing moieties on flavonoid and terpenoid scaffolds can significantly influence their activity as ABC transporter modulators.
  • Various semisynthetic derivatives have demonstrated inhibitory effects on key MDR efflux pumps.
  • These modifications represent a promising strategy for overcoming chemotherapy resistance.

Conclusions:

  • Semisynthetic nitrogen-containing flavonoids and terpenoids are valuable candidates for developing novel MDR reversal agents.
  • Targeting ABC transporters with these modified natural products offers a viable approach to enhance cancer chemotherapy outcomes.
  • Further research into these derivatives could lead to more effective cancer treatment strategies.
Keywords:
ABC-transportersBCRP and MRP1P-gpcancermultidrug resistancenatural productsnitrogen-containing flavonoid derivativesnitrogen-containing terpenoid derivatives

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