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

Authors

Malgorzata Frik, CUNY Brooklyn College
Alberto Martínez, CUNY New York City College of Technology
Benelita T. Elie, CUNY Brooklyn College
Oscar Gonzalo, Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009, Zaragoza, Spain
Daniel Ramírez de Mingo, Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009, Zaragoza, Spain
Mercedes Sanaú, Departamento de Química Inorgánica, Universidad de Valencia, Edificio F, 5th Planta, Calle Dr. Moliner 50, Burjassot, Valencia 46100, Spain
Roberto Sánchez-Delgado, CUNY Brooklyn College
Tanmoy Sadhukha, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States
Swayam Prabha, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States
Joe W. Ramos, Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 701 Ilalo Street, Honolulu, Hawaii 96813, United States
Isabel Marzo, Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009, Zaragoza, Spain
María Contel, CUNY Brooklyn CollegeFollow

Document Type

Article

Publication Date

November 2015

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.

Comments

This work was originally published in Journal of Medical Chemistry, available at doi:10.1021/jm5012337.