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

Abstract

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.