201653-76-1

Usage

Pharmaceutical Applications

NAMI-A has shown activity in the treatment of metastatic cancer and has completed phase I clinical trials in the Netherlands. It has been shown that the complex is relatively nontoxic. Significantly higher doses than cisplatin (above 500 mg/m2/day) lead to side effects such as blisters on the extremities. Within the study, the ruthenium complex was administered intravenously over a period of 3 h in a 0.9% saline solution (pH～4) . The NAMI-A is synthesised by reacting RuCl3?3H20 with HCl and DMSO (dimethylsulfoxide). This reaction results in the trans complex Imidazolium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate(III) (NAMI-A) . It is interesting to note that Imidazolium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate(III) is a paramagnetic compound and the complex is quickly hydrolysed in water. Initially, one chloride ligand is replaced by an aquo ligand, but the DMSO ligand is quickly replaced as well. As previously mentioned, it has been suggested that the complex is activated by bio-reduction of the Ru(III) centre to Ru(II) in the hypoxic environment of cancer cells. There is not much knowledge at present about the biological target for Imidazolium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate(III). It is known that it interacts with the imidazoles of proteins and that the interaction with DNA is only weak, questioning DNA as a primary target for the ruthenium drug.

Upstream product

• 288-32-4 1H-imidazole 

Downstream Products

• 783325-04-2 (Ph₃PCH₂Ph)[trans-RuCl₄(imidazole)(DMSO)] 

Relevant academic research and scientific papers

Kinetics and mechanistic investigation into the possible activation of imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(iii)], NAMI-A, by 2-mercaptoethane sulfonate

Imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(iii)], NAMI-A, is a promising antimetastatic prodrug with high specificity for metastatic cancer cells. Limited activity of NAMI-A against primary tumor suggests that its use in combination with other anticancer drug(s) might present a more desirable therapeutic outcome. The mechanism of activation and action of this prodrug is still largely unknown. The biological targets, as well, have not yet been delineated. The kinetics and mechanism of interaction of NAMI-A with 2-mercaptoethane sulfonate, MESNA, a chemoprotectant, have been studied spectrophotometrically under pseudo-first order conditions of excess MESNA. The reaction is characterized by initial reduction of NAMI-A and formation of dimeric MESNA as evidenced by electospray ionization mass spectrometry. A first order dependence on both NAMI-A and MESNA was obtained and a bimolecular rate constant of 0.71 ± 0.06 M-1 s-1 was deduced. Activation parameters determined (ΔS≠ = -178.12 ± 0.28 J K-1 mol-1, ΔH≠ = 20.64 ± 0.082 kJ mol-1 and ΔG≠ = 75.89 ± 1.76 kJ mol-1 at 37 ± 0.1 °C and pH 7.4) are indicative of formation of an associative intermediate prior to product formation and subsequent hydrolysis of the reduced complex. Our results suggest that MESNA might be able to activate the prodrug while still protecting against toxicity when given in a regimen involving NAMI-A and chemotherapy drug(s) that induce bladder and kidney toxicities. This journal is the Partner Organisations 2014.