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

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

Published In Eur J Med Chem, (2019 Feb 01)

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.

PubMed ID: 30579125

MeSH Terms: 2,2'-Dipyridyl/chemistry*; ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors*; Animals; Antineoplastic Agents/chemistry; Antineoplastic Agents/pharmacology; Biotin/chemistry*; Breast Neoplasms/drug therapy; Breast Neoplasms/pathology; Coordination Complexes/chemistry; Coordination Complexes/pharmacology*; Drug Resistance, Multiple; Humans; Ligands; Ruthenium/chemistry*; Zebrafish