Barbara Serli

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.

Coordination and release of NO by ruthenium–dimethylsulfoxide complexes—implications for antimetastases activity

Abstract Several Ru(II) and Ru(III)–dimethylsulfoxide (DMSO) complexes, that are not cytotoxic in vitro, are endowed with anticancer and, in particular, antimetastatic activity against animal tumor models. One possibility for explaining the activity of such compounds against disseminated tumors is that they interfere with NO metabolism in vivo. Thus, we investigated the reactivity of ruthenium–chloride–DMSO complexes towards NO with the aim of producing well-characterized models to be used as reference compounds in subsequent biomimetic studies. In this contribution, we report on the synthesis, spectroscopic, structural and electrochemical characterization of anionic (e.g. [(DMSO)2H][trans-RuCl4(DMSO-O)(NO)] (1)), neutral (e.g. mer,cis-RuCl3(DMSO-O)2(NO) (2)) and new cationic (e.g. [cis,fac-RuCl2(DMSO-O)3(NO)][BF4] (9)) Ru–DMSO nitrosyls, derived from both Ru(II) and Ru(III)–chloride–DMSO precursors. Coordination of the strong π-acceptor NO favors coordination of DMSO ligands through oxygen (DMSO-O) to avoid competition for π electrons. The reactivity of some Ru–DMSO–NO complexes towards heterocyclic N-ligands, leading to compounds such as [(Im)2H][trans-RuCl4(Im)(NO)] (Im=imidazole, 6) and [cis,mer-RuCl2(py)3(NO)][BF4] (py=pyridine, 10), is also described. The spectroscopic and X-ray structural features for all these complexes are consistent with the {Ru(NO)}6 formulation, that is a diamagnetic Ru(II) nucleus bound to NO+. Electrochemical measurements on the Ru–NO complexes showed that they are all redox active in DMF solutions and the site of reduction is the NO+ moiety. With the exception of 10, the reduced complexes are not stable and rapidly release the NO radical.

Novel mono- and dinuclear ruthenium nitrosyls with coordinated pyrazine

Abstract The synthesis and characterization of some novel mono- and dinuclear ruthenium nitrosyls bearing either terminal ([NBu4][trans-RuCl4(pyz)(NO)] (1a) and [NBu4][cis-RuCl4(pyz)(NO)] (1b)) or bridging pyrazine ([NBu4]2[{trans/cis-RuCl4(NO)}2(μ-pyz)] (trans,trans 2a, cis,cis 2b, trans,cis 2c)) are reported. Compounds 1 and 2 were prepared from the same precursor, [NBu4][trans-RuCl4(dmso-O)(NO)], upon treatment with pyrazine in different ratios. Pure compounds were obtained by crystallization or column chromatography. All species possess the linear {RuII(NO+)}6 moiety, and the NO stretching frequency is quite sensitive to the nature of the trans ligand (either N or Cl). The unbound termini of the pyrazine ligands in compounds 1a and 1b are capable of further reaction with metal centers; treatment of the two isomers with a stoichiometric amount of [Ru(TPP)(CO)(EtOH)] (TPP=tetraphenylporphyrinate) led to the quantitative formation of the unsymmetrical dinuclear species [NBu4][{trans-RuCl4(NO)}(μ-pyz){Ru(TPP)(CO)}] (3a) and [NBu4] [{cis-RuCl4(NO)}(μ-pyz){Ru(TPP)(CO)}] (3b), respectively, in which pyrazine bridges two ruthenium centers in different environments. Thus monomers 1a and 1b can be considered as new examples of complexed bridging ligands that might be used as building blocks in the construction of supramolecular assemblies. The crystal structures of the mononuclear species 1a and 1b, and of the dinuclear species 3a were also determined.

Novel RuIII-DMSO Complexes of the Antiherpes Drug Acyclovir

Treatment of the anionic RuIII precursor X[trans-RuCl4(DMSO-S)2] (X = protonated DMSO, Na+, NH4+) and acyclovir (acv) in various solvents yields two new products mer-[RuCl3(acv)(DMSO-S)(CH3OH)]·0.5CH3OH (1) and mer-[RuCl3(acv)(DMSO-S)(H2O)]·H2O (2) in which hydrogen bonds between the acv purine oxygen and coordinated methanol or water, respectively, play an important role. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Pyridylporphyrins peripherally coordinated to ruthenium-nitrosyls, including the water-soluble Na4[Zn·4′TPyP{RuCl4(NO)}4]: synthesis and structural characterization

Several new ruthenium-nitrosyl conjugates with meso-4′pyridylporphyrins, namely the two anionic isomers [nBu4N][trans-RuCl4(4′MPyP)(NO)] (1) and [nBu4N][cis-RuCl4(4′MPyP)(NO)] (2), the two neutral isomers [mer,trans-RuCl3(4′MPyP)2(NO)] (3) and [mer,cis-RuCl3(4′MPyP)2(NO)] (4), and the tetraruthenated adduct [nBu4N]4[4′TPyP{RuCl4(NO)}4] (5) were obtained by reaction of [nBu4N][trans-RuCl4(dmso-O)(NO)] with 4′MPyP and 4′TPyP (meso-4′monopyridylporphyrin and meso-4′tetrapyridylporphyrin, respectively). The X-ray structures of 2, 4, and 5 are described. Exchange of nBu4N+ for Na+ eventually led to the water-soluble tetraruthenated porphyrin Na4[Zn·4′TPyP{RuCl4(NO)}4] (6·Zn).

Novel Unsymmetrical Ru(III) and Mixed-valence Ru(III)/Ru(II) Dinuclear Compounds Related to the Antimetastatic Ru(III) Drug NAMI-A.

In this paper we report the stepwise preparation and the characterization of new unsymmetrical monoanionic Ru(III) dinuclear compounds, [NH4][{trans-RuCl4(Me2SO-S)}(μ-L){mer-RuCl3(Me2SO-S)(Me2SO-O)}] (L = pyz (1), pym (2)). By a similar synthetic approach we also prepared new mixed-valence Ru(III)/Ru(II) dinuclear compounds of formula [NH4][{trans-RuCl4(Me2SO-S)}(μ-pyz){cis,cis,cis-RuCl2(Me2SO-S)2(CO)}] (L = pyrazine (pyz, 3), pyrimidine (pym, 4)). Moreover, we describe the chemical behavior of compounds 1-4 in physiological solution, also after complete reduction (with ascorbic acid) to the corresponding Ru(II)/Ru(II) species. Overall, the chemical behavior of 1 and 2 after reduction resembles that of the corresponding dianionic and neutral dinuclear species, [{trans-RuCl3(Me2SO-S)}2(μ-L)]2−and [{mer-RuCl3(Me2SO-S)(Me2SO-O)}2 (μ-L)]. On the other hand, the mixed-valence dinuclear compounds 3 and 4, owing to the great inertness of the cis,cis,cis-RuCl2(Me2SO-S)2(CO)(1/2μ-L) fragment, behave substantially like the mononuclear species [trans-RuCl4(Me2SO-S)(L)]− in which the terminally bonded L ligand can be considered as bearing a bulky substituent on the other N atom.