A series of 18 ruthenium(III) complexes, structurally related to the selective antimetastatic drug Na[trans-RuCl4(DMSO)Im], and characterized by the presence of sulfoxide and nitrogen-donor ligands were tested on TLX5 lymphoma and some of them on MCa mammary carcinoma to evaluate the dependence of the degree of cytotoxicity and of antimetastatic activity on the chemical properties. In vitro cytotoxicity is present only at high concentrations (> 10(-4) M), depends upon lipophilicity and is markedly affected by the presence of 5% serum or plasma samples in the culture medium. The comparison of the effects on in vitro cytotoxicity with in vivo antitumor and antimetastatic action points out that these compounds reduce metastasis formation by a mechanism unrelated to a direct tumor cell cytotoxicity. If on one hand Na[trans-RuCl4(TMSO)Iq], the compound that shows the most potent in vitro cytotoxic effects, is the least effective against metastases, on the other Na[trans-RuCl4(DMSO)Im], the compound that better reduces metastasis formation, is rather devoid of cytotoxic effects on tumor cells kept in vitro. In particular, Na[trans-RuCl4(DMSO)Im] seems to distinguish between artificially induced metastases and spontaneous metastases and reduces only the former by a cytotoxic mechanism. Out of all the tested compounds, with the exception of Na[trans-RuCl4(DMSO)Ox], Na[trans-RuCl4(DMSO)Im] is confirmed to be the most selective antimetastatic agent of the group.

01 Jan 1993·Inorganica Chimica Acta

Synthesis and characterization of two new classes of ruthenium(III)-sulfoxide complexes with nitrogen donor ligands (L): Na[trans-RuCl4(R2SO)(L)] and mer, cis-RuCl3(R2SO)(R2SO)(L). The crystal structure of Na[trans-RuCl4(DMSO)(NH3)] · 2DMSO, Na[trans-RuCl4(DMSO)(Im)] · H2O, Me2CO (Im = imidazole) and mer, cis-RuCl3(DMSO)(DMSO)(NH3)

Author: Alessio, E. ; Attia, W. M. ; Calligaris, M. ; Balducci, G. ; Mestroni, G. ; Lutman, A.

Na[trans-RuCl₄(R₂SO)(L)] and mer,cis-[RuCl₃(R₂SO)(R₂SO)(L)] (L = nitrogen ligand) were prepared and their spectroscopic characterization in the solid state (IR) and in solution (NMR, UV-visible) is described.The cyclic voltammetry of the complexes performed in aqueous solution shows in every case a monoelectronic rapid Ru(III) /Ru(II) electron transfer.The observed formal potentials are much more pos. than those reported for other Ru(III) complexes.The net charge, together with the π acidic ability of DMSO-S, are the factors responsible for this behavior.The crystal structures of Na[trans-RuCl₄(DMSO-S)(NH₃)]·2DMSO (5a) (triclinic, space group P1̅, Z = 2, R = 0.039), Na[trans-RuCl₄(DMSO-S)(Im)]·H₂O·Me₂CO (5b) (triclinic, space group P1̅, Z = 2, R = 0.031) and mer,cis-RuCl₃(DMSO-S)(DMSO-O)(NH₃) (6a) (monoclinic, space group P2₁/n, Z = 4, R = 0.022) were determinedIn 5a and 5b, the DMSO ligand is S-bonded to Ru, with Ru-S bond distances (trans to N) of 2.2797(7) and 2.2956(6) Å, resp., while in 6a, one DMSO, trans to N, is S-bonded (Ru-S, 2.2714(6) Å), and the other, trans to Cl, is O-bonded (Ru-O, 2.070(2) Å).The Ru-Cl bond distance trans to O is 2.3207(7) Å.The Ru-Cl bond distances trans to Cl are similar in all three compounds averaging 2.343(6) Å.The antitumor activity of some of the new compounds is currently under investigation.Their redox potentials suggest the possibility that they might undergo an easy biol. reduction in vivo.

01 Feb 1992·Anti-Cancer Drugs

Effects of the Ru(III) complexes [mer-RuCl3(DMSO)2Im]° and Na[trans-RuCl4(DMSO)Im] on solid mouse tumors

Article

Author: Sava, Gianni ; Mestroni, Giovanni ; Alessio, Enzo ; Pacor, Sabrina

The effects of two new Ru(III) complexes, [mer-RuCl3(DMSO)2Im] degrees and Na[trans-RuCl4(DMSO)Im], were investigated on primary tumor growth and on the survival time using three solid metastasizing tumors of the mouse: Lewis lung carcinoma, B16 melanoma and MCa mammary carcinoma. Na[trans-RuCl4(DMSO)Im] appears to be the most promising compound, in that: (1) it is soluble in water and therefore easy to handle in comparison with the neutral species [mer-RuCl3(DMSO)2Im]degrees or to the already described BBR2382; (2) similarly to cisplatin, though at a lower level, it reduces tumor growth in its primary site in each tumor model employed; (3) unlike cisplatin, it increases the life span of tumor-bearing hosts in all tumors used, independently of the effects on primary tumor growth; and (4) it is also effective in reducing spontaneous metastasis formation when the effects on primary tumor growth are completely absent. Dimethylsulfoxide (DMSO), used for solubilizing poorly water-soluble compounds (i.e. [mer-RuCl3(DMSO)2Im]degrees) or for stabilizing the compound in the solution before injection (i.e. Na[trans-RuCl4(DMSO)Im]), reduces the anti-tumor potency. Conversely, the antitumor effects of Na[trans-RuCl4(DMSO)Im] are more pronounced in mice hydrated with isotonic saline. We conclude that Na[trans-RuCl4(DMSO)Im] is a good candidate for further investigations aimed at ascertaining the mechanism of the anti-metastatic activity and of the positive effects on survival time of mice bearing solid metastasizing tumors.

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Indication	Highest Phase	Country/Location	Organization	Date
Lung Cancer	Discovery	Germany	Boehringer Mannheim GmbH	-

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