A Comparison of the Cyanide-Scavenging Capabilities of Some Cobalt-Containing Complexes in Mice

Abstract

Four cobalt-containing macrocyclic compounds previously shown to ameliorate cyanide toxicity have been comparatively evaluated with an acute sublethal toxicity model in conscious (unanesthetized) adult male Swiss-Webster mice. All of the compounds (the cobalt-corrins cobalamin and cobinamide, a cobalt-porphyrin, plus a cobalt-Schiff base macrocycle) given 5 min prior to the toxicant dose significantly decreased the righting-recovery time of cyanide-intoxicated mice, but the doses required for maximal antidotal effect varied. Additionally, all of the compounds tested significantly reduced the righting-recovery time when administered at either 1 or 2 min after cyanide intoxication, but none of the compounds tested significantly reduced the righting-recovery time when delivered 5 min after the toxicant dose. Using the lowest effective dose of each compound determined during the first (prophylactic) set of experiments, neuromuscular recovery following cyanide intoxication in the presence/absence of the cobalt-based antidotes was assessed by RotaRod testing. All the compounds tested accelerated recovery of neuromuscular coordination, and no persistent impairment in any group, including those animals that received toxicant and no antidote, was apparent up to 2 weeks postexposures. The relative effectiveness of the cobalt compounds as cyanide antidotes are discussed and rationalized on the basis of the cyanide-binding stoichiometries and stability constants of the Co(III) cyano adducts, together with consideration of the rate constants for axial ligand substitutions by cyanide in the Co(II) forms.

A Cobalt Schiff-Base Complex as a Putative Therapeutic for Azide Poisoning

“…The protective effect of CoN 4 [11.3.1] against cyanide toxicity has previously been demonstrated in a mouse model. 12,13 When CoN 4 [11.3.1]Br 2 (37 mg/kg) was given at 5 min post sodium azide, all the mice recovered, the majority did not knockdown (71%), and those that did (29%) recovered by 12 min (Table 1). These results clearly demonstrate that CoN 4 [11.3.1] is a potential antidote to azide toxicity, providing encouragement for the further development of scavenger-based therapeutics.…”

“…The detoxification of cyanide by cobalt complexes has recently been suggested to consist of the toxicant binding to the reduced (substitution labile) Co­(II) forms, resulting in lowering of their oxidation potentials; this in turn facilitates oxidation to the (substitution inert) Co­(III) cyanide adducts that may then be excreted. ,− That is, bound cyanide becomes trapped in kinetically stable forms from which it is slow to dissociate, preventing systemic redistribution of the toxicant and, thereby, nullifying its toxicity . A somewhat similar mechanism of decorporation is plausibly operating in the case of the current preliminary experiments with azide intoxicated mice given Co­(II)­N 4 [11.3.1] (Table ) but differing in detail.…”

“…In our previous studies concerning the amelioration of cyanide toxicity by CoN 4 [11.3.1] in mice, we found the complex to be an efficacious antidote when given either 5 min before or 2 min after an LD 40 dose of cyanide (5 mg/kg NaCN). 12,13 The cobalt macrocycle was shown to bind two molecules of cyanide cooperatively, 13 and extensive studies in mice showed it to be at least as good an antidote as cobinamide while measurably better than hydroxocobalamin. 12 Consequently, because azide is a slower acting toxicant, it is perhaps not surprising that preliminary experiments with CoN 4 [11.3.1] in mice indicate that it will function as an azide antidote when given at least 5 min after the toxicant (Table 1).…”

“…10,11 Recently, we have demonstrated a cobalt containing Schiffbase macrocyclic compound, Co(II)-2,12-dimethyl-3,7,11,17tetraazabicyclo [11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl dibromide (CoN 4 [11.3.1]), to be an effective cyanide scavenger in mice. 12,13 Here, we explore whether CoN 4 [11.3.1] might also be an efficacious antidote toward azide toxicity by virtue of its anionic ligand-binding (scavenging) capability. The kinetics of the reaction between azide anion and the complex have been investigated at physiologically relevant pH and temperature by stopped-flow spectrophotometry.…”

Antidotal efficacies of the cyanide antidote candidate dimethyl trisulfide alone and in combination with cobinamide derivatives

“…Cobinamide is a cobalamin derivative, which has the advantage of allowing two CNs to bind to the cobalt ion of the Corrine ring . Cobinamide is 3-10 times more potent than hydroxocobalamin in mouse, rabbit, and swine models (Chan et al, 2015;Chan et al, 2018;Cronican et al, 2018). It is reported that nitrocobinamide derivatives are very stable and are absorbed well after IM injection (Chan et al, 2015).…”