Mechanisms of cyanide and azide binding to cobalt complexes relevant to their antidotal action

[摘要] In recent years, the possibility of mass casualties resulting from acts of chemical terrorism has emerged as a growing public health issue. Due in part to their wide availability and potential simplicity of deployment, cyanide and azide are two toxic agents that have already been nefariously employed to a limited extent and, moreover, are regarded as substances of concern in relation to possible acts of terrorism by the Department of Homeland Security. In the US, the two approved cyanide therapies, nitrite in combination with thiosulfate and the FDA-labeled hydroxocobalamin, are not suitable for use in mass casualty situations; while, no antidote is available for azide.Recently, the cobalt Schiff-base complex 2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl Co(II/III) di/tribromide (CoN4[11.3.1]) has been shown to have antidotal effectiveness toward cyanide and azide in mice. The reaction mechanism(s) by which CoN4[11.3.1] detoxifies cyanide and azide, however, has(have) remained speculative until now – presenting something of a barrier to the rational development of the next generation of antidotes.In this dissertation, the kinetics of the binding of cyanide and azide to the Co(II)N4[11.3.1] compound studied under anaerobic conditions using stopped-flow spectrophotometry are reported. In addition, the reduction kinetics of Co(III)N4[11.3.1] by ascorbate have been examined as well as the oxidation of Co(II)N4[11.3.1], the dicyano-Co(II)N4[11.3.1] and the diazido-Co(II)N4[11.3.1] by molecular oxygen.Mechanisms of cyanide and azide binding to CoN4[11.3.1] are discussed as well as the possible utility of CoN4[11.3.1] as a cyanide or azide antidote.

[发布机构] the University of Pittsburgh