Cyanide Scavenging by a Cobalt Schiff-Base Macrocycle: A Cost-Effective Alternative to Corrinoids

Abstract

The complex of cobalt(II) with the ligand 2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)-2,11,13,15-pentaene (CoN4[11.3.1]) has been shown to bind two molecules of cyanide in a cooperative fashion with an association constant of 2.7 (±0.2) × 105. In vivo, irrespective of whether it is initially administered as the Co(II) or Co(III) cation, EPR spectroscopic measurements on blood samples show that at physiological levels of reductant (principally ascorbate) CoN4[11.3.1] becomes quantitatively reduced to the Co(II) form. However, following addition of sodium cyanide, a dicyano Co(III) species is formed, both in blood and in buffered aqueous solution at neutral pH. In keeping with other cobalt-containing cyanide-scavenging macrocycles like cobinamide and cobalt(III) meso-tetra(4-N-methylpyridyl)-porphine, we found that CoN4[11.3.1] exhibits rapid oxygen turnover in the presence of the physiological reductant ascorbate. This behavior could potentially render CoN4[11.3.1] cytotoxic and/or interfere with evaluations of the antidotal capability of the complex toward cyanide through respirometric measurements, particularly since cyanide rapidly inhibits this process, adding further complexity. A sublethal mouse model was used to assess the effectiveness of CoN4[11.3.1] as a potential cyanide antidote. The administration of CoN4[11.3.1] prophylactically to sodium cyanide-intoxicated mice resulted in the time required for the surviving animals to recover from “knockdown” (unconsciousness) being significantly decreased (3 ± 2 min) compared to that of the controls (22 ± 5 min). All observations are consistent with the demonstrated antidotal activity of CoN4[11.3.1] operating through a cyanide-scavenging mechanism, which is associated with a Co(II) → Co(III) oxidation of the cation. To test for postintoxication neuromuscular sequelae, the ability of mice to remain in position on a rotating cylinder (RotaRod test) was assessed during and after recovery. While intoxicated animals given CoN4[11.3.1] did recover ~30 min more quickly than controls given only toxicant, there were no indications of longer-term problems in either group, as determined by continuing the RotaRod testing up to 24 h after the intoxications and routine behavioral observations for a further week.

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

“…The addition of Co­(III)­N 4 [11.3.1] to mouse blood was previously shown to result in its reduction to the Co­(II) form . We, therefore, studied the stoichiometry and determined the equilibrium constant for the binding of azide to Co­(II)­N 4 [11.3.1].…”

“…We routinely employ the righting recovery behavior of mice to assess the ability of potential antidotes to ameliorate sublethal doses of toxicants (especially cyanide). ,, In the present study, mice were injected (ip) with sodium azide ( t = 0) and then, after “knockdown” (loss of consciousness), placed on their backs and the time until they “righted” themselves onto four feet recorded. Mice given sodium azide exhibited a rather steep response curve (Figure ): 25 mg/kg showed no effect, while 30 mg/kg was essentially a lethal dose.…”

“…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.…”

“…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.…”

Modified vitamin B12 derivatives with a peptide backbone for biomimetic studies and medicinal applications

“…This short review focuses on the author's group efforts in the development of modified B 12 derivatives with a peptide backbone as models of cofactor-protein complexes as well as for medicinal and biological applications. For more comprehensive insight into the topic including the uptake, metabolism and reactivity of Cbls in biological systems [3,7,8,17,[19][20][21], the development of B 12 derivatives as biomimetic models [22][23][24][25][26][27][28], or the use of Cbls for medical [2,[29][30][31][32][33][34][35][36][37][38][39][40] and analytical applications [41][42][43][44][45][46], the interested reader is referred to the original literature as well as to several excellent reviews and book chapters [2,3,8,[47][48][49][50][51].…”