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

一种带有联吡啶-生物素配体的新型钌-环戊二烯基化合物对 P-gp 活性具有前所未有的抑制作用

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作者: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

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.

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