In vitro and in vivo evaluation of water-soluble iminophosphorane ruthenium(II) compounds. A potential chemotherapeutic agent for triple negative breast cancer

Malgorzata Frik, Alberto Martínez, Benelita T. Elie, Oscar Gonzalo, Daniel Ramírez De Mingo, Mercedes Sanaú, Roberto Sánchez-Delgado, Tanmoy Sadhukha, Swayam Prabha, Joe W. Ramos, Isabel Marzo, María Contel

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54 Scopus citations

Abstract

A series of organometallic ruthenium(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70-100 mg/mL). Most compounds (especially highly water-soluble 2) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of 2 on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption of 2 in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo.

Original languageEnglish (US)
Pages (from-to)9995-10012
Number of pages18
JournalJournal of medicinal chemistry
Volume57
Issue number23
DOIs
StatePublished - Dec 11 2014

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