Unprecedented inhibition of P-gp activity by a novel ruthenium-cyclopentadienyl compound bearing a bipyridine-biotin ligand

Leonor Côrte-Real, Brittany Karas, Patrícia Gírio, Alexis Moreno, Fernando Avecilla, Fernanda Marques, Brian T. Buckley, Keith R. Cooper, Cathleen Doherty, Pierre Falson, M. Helena Garcia, Andreia Valente

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Two new ruthenium complexes, [Ru(η5-Cp)(PPh3)(2,2’-bipy-4,4’-R)]+ with R = -CH2OH (Ru1) or dibiotin ester (Ru2) were synthesized and fully characterized. Both compounds were tested against two types of breast cancer cells (MCF7 and MDA-MB-231), showing better cytotoxicity than cisplatin in the same experimental conditions. Since multidrug resistance (MDR) is one of the main problems in cancer chemotherapy, we have assessed the potential of these compounds to overcome resistance to treatments. Ru2 showed exceptional selectivity as P-gp inhibitor, while Ru1 is possibly a substrate. In vivo studies in zebrafish showed that Ru2 is well tolerated up to 1.17 mg/L, presenting a LC50 of 5.73 mg/L at 5 days post fertilization.

Original languageEnglish (US)
Pages (from-to)853-863
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume163
DOIs
StatePublished - Feb 1 2019

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Anticancer agents
  • Multidrug resistance
  • P-gp inhibitor
  • Ruthenium organometallic compounds

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