Giovanni Mestroni

Ruthenium antimetastatic agents

NAMI-A, i. e. (imH)[trans-RuCl(4)(dmso-S)(im)] (im = imidazole, dmso = dimethylsulfoxide), is a Ru(III) complex that, after extensive preclinical investigations that evidenced its remarkable and specific activity against metastases, has recently and successfully completed a Phase I trial (first ruthenium complex ever to reach clinical testing). This review article, after a brief summary of the main chemical and pharmacological aspects of NAMI-A, focuses on the development of new classes of ruthenium complexes originated from the NAMI-A frame. In particular, the chemical and biological features of the following classes of compounds will be treated: i) NAMI-A-type complexes, derived from NAMI-A by changing the nature of the N-ligand, ii) dinuclear NAMI-A-type compounds containing heterocyclic bridging N-N ligands, iii) new Ru-dmso nitrosyls broadly derived from NAMI-A-type complexes. Several of these new compounds were found to have antimetastatic activity comparable to, or even better than, NAMI-A; however, the nature of the target(s) responsible for the antimetastatic activity remains unclear. Common to any type of NAMI-A-type compound, both monomeric and dimeric, cell cytotoxicity (which is generally very low) is not sufficient to explain their potent and peculiar antitumor activity. All active NAMI-A-type compounds share the capacity to modify important parameters of metastasis such as tumor invasion, matrix metallo proteinases activity and cell cycle progression.

Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A

The influence of chemical stability on the antimetastatic ruthenium(III) compound imidazolium trans-imidazoletetrachlorodimethylsulphoxideruthenium(III) (NAMI-A) in aqueous solution was studied both in vitro and in vivo. The loss of dimethyl-sulphoxide (DMSO) ligand from the compound was tested by using a NAMI-A solution acidified with HCl at pH 3.0 and aged for 0, 4, 8 and 24 h prior to intraperitoneal (i.p.) injection into CBA mice bearing advanced MCa mammary carcinoma. The activity of NAMI-A on lung metastases showed no change even after the loss of DMSO ligand from up to 50% of the molecules. The reduction of NAMI-A did not modify the number of KB cells blocked in the S+G2M phases, independent of whether the reduction occurred outside the cells or after loading the cells with the compound prior to treatment with the reductants (ascorbic acid, glutathione or cysteine). In vivo, the complete reduction of NAMI-A with equivalent amounts of ascorbic acid, glutathione or cysteine prior to administration to mice bearing advanced MCa mammary carcinoma was more active than NAMI-A alone. The data show that NAMI-A, although undergoing a series of chemical modifications, maintains its antimetastatic activity in a broad range of experimental conditions.

Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex

Imidazolium trans-imidazoledimethylsulphoxidetetrachlororuthenate ImH[trans-RuCl4 (DMSO)Im] (NAMI-A), a ruthenium compound that replaces Na+ with ImH+ in the molecule of Na[trans-RuCl4 (DMSO)Im] (NAMI), was studied for the anti-metastasis effects in models of solid metastasizing tumours of the mouse. NAMI-A, given i.p. at 35 mg/kg/day for six consecutive days, a dose equimolar to that of NAMI, to mice bear-ing Lewis lung carcinoma and MCa mammary carcinoma, markedly reduces lung metastasis weight by 80-90%, with an effect equal or even superior to that of NAMI, depending on the experimental system adopted. Correspondingly, NAMI-A increases the content of connective tissue in the tumour matrix, around blood vessels, and in the tumour capsule, augments the percentage of tumour cells in G 2 /M phase and reduces the amount of CD45 cells infiltrating the tumour parenchyma. The effects of the same doses on spleen lymphocytes correspond to an increase of CD8 subset without any change of t he distribution of cells in G 0 /G 1 , S and G 2 /M phases. The study shows that NAMI-A behaves similarly to NAMI on the several parameters examined in com-parison experiments and therefore we suggest to credit NAMI-A with all the biological actions already described for NAMI during the last 3 years. The replacement of Na+ with ImH+ therefore, besides the better chemical stability of the molecule, confers to [trans-RuCl4 (DMSO)Im] - a closer similarity with a true drug to be used in humans, and suggests this molecule for future studies of preclinical toxicology and phase I and II clinical trials.© Rapid Science Ltd.

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)

Abstract In this paper we report the synthesis of two new classes of chloride-sulfoxide-Ru(III) derivatives containing a nitrogen ligand (L) of general formula: Na[trans-RuCl4(R2SO)(L)] and mer, cis-RuCl3(R2SO)(R2SO)(L). Their spectroscopic characterization in the solid state (IR) and in solution (NMR, UVVis) is also described. The cyclic voltammetry of the complexes performed in aqueous solution shows in every case a monoelectronic and rather rapid Ru(III)/Ru(II) electron transfer. The observed formal potentials are much more positive than those reported for other Ru(III) complexes. The net charge, together with the, π acidic ability of DMSO, are the factors responsible for this behaviour. The crystal structures of Na[trans-RuCl4(DMSO)(NH3)] · 2DMSO (5a), Na[trans-RuCl4(DMSO)(Im)] · H2O, Me2CO 5b and mer, cis-RuCl3(DMSO)(DMSO)(NH3) (6a) have been determined by three dimensional X-ray analyses. Crystal data are: a = 9.578(2), b = 12.480(2), c = 9.594(6) A, α = 104.33(3), β = 119.04(2), γ = 80.71(3)°, triclinic, space group P 1 , Z = 2 for 5a; a = 10.790(4), b = 11.411(4), c = 7.658(4) A, α = 105.92(3), β =93.61(1), γ = 83.50(3)°, triclinic, space group P 1 , Z = 2 for 5b; a = 10.110(3), b = 9.718(3), c = 14.101(3) A, β = 108.89(3)°, monoclinic, space group P21/n, Z = 4 for 6a. Least-squares refinement based on 4897 5a, 4932 5b and 3152 6a independent reflections converged to R = 0.039, 0.031 and 0.022, respectively. In 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) A, respectively, while in 6a, one DMSO, trans to N, is S-bonded (RuS, 2.2714(6) A), and the other, trans to Cl, is O-bonded (RuO, 2.070(2) A). The RuCl bond distance, trans to O, is 2.3207(7) A. The RuCl bond distances, trans to Cl, are similar in all three compounds averaging 2.343(6) A. Relevance in the synthesis of the new derivatives comes from the known antitumor properties of isostructural Ru(III) complexes with heterocyclic nitrogen ligands. The antitumor activity of some of the new compounds are currently under investigation. Their redox potentials suggest the possibility that they might undergo an easy biological reduction in vivo.

Organometallic derivatives of cobalt chelates of bis(acetylacetone) ethylendiamine

Abstract The preparations of the complexes Co II (BAE), [Co III (BAE)L 2 ]X, Co III (BAE)LX and of some new stable organocobalt complexes RCo III (BAE) and RCo III (BAE)·H 2 O are described (BAE = bis(acetylacetone) ethylendiamine; L = NH 3 , C 6 H 5 CH 2 NH 2 , C 6 H 5 N, (C 6 H 5 ) 3 P; X = Cl, Br). The UV and visible absorption spectra are reported. The compounds RCo(BAE) appear to be new examples of penta-coordinated organocobalt complexes and constitute further evidence for the stabilization of the cobalt-carbon bond by chelation. The labilization of the sixth ligand by the alkyl or aryl group in the trans position is pointed out.

Vitamin b12 model compounds - cobalt chelates of bis(diacetylmonoxime -imino)propane 1–3

Abstract The preparation and properties of a new series of Vit. B 12 model compounds, - cobalt chelates of bis(diacetylmonoximeimino)- propane 1,3 are reported. The synthesis of organometallic derivatives as model molecules of alkylcobalamins is discussed. Rationalization of the coordination chemistry of cobalt atom in these and other previously reported model molecules is attempted by consideration of the influence of equatorial ligands on the axial position and the trans effect between axial ligands.

Reduction of lung metastasis by ImH[trans-RuCl4(DMSO)Im]: mechanism of the selective action investigated on mouse tumors.

NAMI-A (imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, ImH[trans-RuCl4(DMSO)Im]) is a new ruthenium compound active against lung metastasis of solid metastasizing tumors. We have tested this compound in mice with Lewis lung carcinoma or MCa mammary carcinoma in order to compare the effects on primary tumor and lung metastases with possible alterations of cell cycle distribution of tumor cells. We have also investigated whether there were unequal tissue accumulations of the compound itself at different dose levels ranging from 17.5 to 70 mg/kg/day given for six consecutive days. NAMI-A caused a reduction of metastasis weight larger than that of metastasis number; we explain this finding as the capacity of NAMI-A to selectively interfere with the growth of metastases already settled in the lungs. However, this specificity is not simply related to a larger concentration of NAMI-A in the lungs than in other tissues. Following i.p. treatment, NAMI-A rapidly disappeared from the peritoneal cavity; its low blood concentration may be caused by rapid renal clearance. These data provide further evidence for a selective anti-metastasis effect of the ruthenium complex NAMI-A. The reduction of lung metastasis is followed by a significant prolongation of the hosts life-time expectancy, indicating a therapeutic benefit of NAMI-A on lung metastases from solid tumors.

Antineoplastic activity and toxicity of an organometallic complex of ruthenium(II) in comparison with cis-PDD in mice bearing solid malignant neoplasms

The antineoplastic activity of an organometallic complex of ruthenium(II), [cis-RuCl2(DMSO)4]o, has been examined in comparison with that of cis-PDD, using three metastasizing tumors of the mouse: Lewis lung carcinoma, B16 melanoma and MCa mammary carcinoma. [cis-RuCl2(DMSO)4]o significantly reduces primary tumor growth in all the tumors tested, and its activity is similarly pronounced at three different dosages in mice bearing Lewis lung carcinoma. On the contrary, the survival time of animals having i.v. or i.m. tumor implants are only moderately increased, and also in the case of combined treatments with surgery. The antineoplastic activity of cis-PDD appears to be less pronounced than that of [cis-RuCl2(DMSO)4]o, and is limited to mice bearing B16 melanoma, which, among the three tumors used, appears to be naturally more responsive to cis-PDD and [cis-RuCl2(DMSO)4]o. The use of [cis-RuCl2(DMSO)4]o appears advantageous over that of cis-PDD since, unlike cis-PDD, its antineoplastic effects have been obtained at dosages with reduced host toxicity, indicated by the absence of significant hematological toxicity and toxicity for normal proliferating tissues.

Organometallic derivatives of cobalt(III) chelates of bis(salicylaldehyde) ethylenediimine

Abstract The preparations of stable organocobalt chelates of bis(salicylaldehyde) ethylenediimine, (salen), RCo(salen)L and RCo(salen)(R = CH3, C2H5, C3H7, C4H9, C6H5; L = H2O, NH3, pyridine, benzimidazole) are described. The UV and visible absorption spectra are reported and briefly discussed. Evidence for the photolability of the complexes is presented. Chemical and physico-chemical behaviour of the complexes confirm the stabilization of the cobalt-carbon bond by formation of conjugate chelate rings.

Reductive carbonylation of nitroaromatic compounds to urethanes catalyzed by [Pd(1,10-phenanthroline)2][PF6]2 and related complexes

Abstract Pd(II) complexes with 1,10-phenanthroline (phen) derivatives of general formula [Pd(chel)2][PF6]2 (chel=phen, 4,7Me2-phen, 4,7Ph2-phen, 3,4,7,8Me4-phen (TMphen), 4,7(MeO)2-phen) show high activity and selectivity in the catalytic synthesis of aromatic urethanes under relatively mild reaction conditions and without any added cocatalyst. Various trends have been studied with the aim to improve the efficiency of the system and to shed light on the nature of the catalyst.