In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer

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• 作者：Malgorzata Frik ; Alberto Mart铆nez ; Benelita T. Elie ; Oscar Gonzalo ; Daniel Ram铆rez de Mingo ; Mercedes Sana煤 ; Roberto S谩nchez-Delgado ; Tanmoy Sadhukha ; Swayam Prabha ; Joe W. Ramos ; Isabel Marzo ; Mar铆a Contel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9995-10012
• 全文大小：652K
• ISSN：1520-4804

文摘

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鈥?00 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.