Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 23, Pages 9995-10012Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm5012337
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Funding
- National Cancer Institute (NCI) [1SCICA182844]
- National Institute of General Medical Sciences (NIGMS) [SC2GM082307, 1SC1GM089558, ROIGM088266-A1]
- Ministerio de Economia y Competitividad [SAF2010-1490]
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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.
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