Appraisal of the redox behaviour of the antimetastatic ruthenium(iii) complex [ImH][RuCl4(DMSO)(Im)], NAMI-A

Abstract

The imidazolium trans-tetrachloro(dimethylsulfoxide)imidazoleruthenate(III) complex [ImH][Ru(III)Cl(4)(DMSO)(Im)], NAMI-A, has shown an interesting antimetastatic activity. Since Ru(III) complexes are coordinatively more inert than the corresponding Ru(II) derivatives, an "activation by reduction" mechanism has been proposed to explain the biological activity of NAMI-A, thus acting as a pro-drug. We report here an electrochemical study on NAMI-A in aqueous solutions which emphasizes the structural and chemical consequences accompanying the easy Ru(III)/Ru(II) electron transfer (e.g., axial imidazole/water exchange in acidic solution in the short timescale of cyclic voltammetry followed by equatorial chloride/water exchange in the longer timescale of macroelectrolysis).

Differences in structure, physiological stability, electrochemistry, cytotoxicity, DNA and protein binding properties between two Ru(III) complexes

“…No apparent cleavage can be detected using sodium ascorbate and reduced glutathione as controls (lane 2 and lane 3). The addition of sodium ascorbate does not modify the cleavage ability of the complex (lane 4-6), and actually, the cleavage ability is inhibited by the addition of reduced glutathione (lane [8][9][10]. The possibility of the oxidative pathway is ruled out by the fact that the addition of sodium ascorbate makes no difference.…”

“…Although the antitumor mechanism of ruthenium compounds has not been unequivocally identified, several factors are thought to be responsible for their pharmacological activity: (1) activation by reduction: the in vitro activity of a homologous series of Ru(III) complexes is found to be increased with the increasing ease of reduction [10,11], especially for the KP1019 species; (2) DNA binding mode and affinity: DNA is supposed to be one of the target for the ruthenium-based anticancer drugs. DNA binding plays an important role for Ru(II)-arene organometallic complexes, which can interact with DNA by direct coordination to the bases, intercalation and stereospecific Hbonding [12], while other targets such as plasma proteins and glutathione are thought to be more important in the action of certain Ru(III) complexes, such as NAMI-A and its derivatives [13,14]; (3) hydrolysis of leaving groups: it is thought that for both NAMI-A and KP1019, the chloride ligands are substituted by water molecules in vivo, which subsequently undergo substitution by the nucleobases of DNA.…”

Synthesis, characterization, DNA-binding and spectral properties of complexes [Ru(L)4(dppz)]2+ (L=Im and MeIm)

“…However, the studies on some monodentate co-ligands, in particular, on some functional monodentate co-ligands, are still less found [15][16][17]. As is well-known, imidazole and its derivatives used as DNA model bases have potential biological activities [18][19][20][21] and the Ru(II)-imidazole and their derivatives have been proven to have antitumor [22][23][24] and immunosuppressive activity [25]. Although complexes [Ru(bpy) 2 (L) 2 ] 2+ (L = 1-methylimidazole or its derivatives) were early synthesized [26], so far the report on their DNA-binding or spectral properties has not been found yet, particularly, the study on Ru(II)-dppz complexes with four imidazole as co-ligands has not been reported yet.…”

In vitro and in vivo biological activity screening of Ru(III) complexes involving 6-benzylaminopurine derivatives with higher pro-apoptotic activity than NAMI-A

“…This means that biological reducing agents, e.g. glutathione or ascorbic acid, may be capable of reducing the Ru(III) species to the corresponding Ru(II) ones [60]. According to this hypothesis, the accessible reduction potential for in vivo activity of Ru(III) complexes should be in the range of 〈-400 mV; +800 mV〉 vs NHE [61].…”