In Vitro and in Vivo Evaluation of Ruthenium(II)−Arene PTA Complexes

• Published in: Journal of medicinal chemistry Vol. 48; no. 12; pp. 4161 - 4171
• Main Authors: Scolaro, Claudine, Bergamo, Alberta, Brescacin, Laura, Delfino, Riccarda, Cocchietto, Moreno, Laurenczy, Gábor, Geldbach, Tilmann J, Sava, Gianni, Dyson, Paul J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16.06.2005
• Subjects: Adamantane - analogs & derivatives; Adamantane - chemistry; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Benzene Derivatives - chemistry; Biological and medical sciences; Buffers; Cell Line, Tumor; DNA - chemistry; Female; General aspects; Humans; Hydrolysis; Lung Neoplasms - drug therapy; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Mice, Inbred CBA; Organometallic Compounds - chemical synthesis; Organometallic Compounds - pharmacokinetics; Organometallic Compounds - pharmacology; Organophosphorus Compounds - chemistry; Pharmacology. Drug treatments; Ruthenium - metabolism; Sodium Chloride; Solutions; Structure-Activity Relationship; Tissue Distribution; Xenograft Model Antitumor Assays; Antineoplastic agent; Divalent metal Complexes; Arene; Rodentia; Cytotoxicity; Molecular interaction; Antimetastatic agent; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Mouse; Animal; DNA; Chloro complex; Hapto complex; Platinoid Complexes; Mammary gland; Pharmacokinetics; Chemical synthesis; Tumor cell; Ruthenium II Complexes
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050015d

The antitumor activity of the organometallic ruthenium(II)−arene complexes, RuCl2(η6-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)−arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma in the absence of a corresponding action at the site of primary tumor growth. Pharmacokinetic studies of RAPTA-C indicate that ruthenium is rapidly lost from the organs and the bloodstream.