Effect of Ascorbate on the Cyanide-Scavenging Capability of Cobalt(III) meso-Tetra(4-N-methylpyridyl)porphine Pentaiodide: Deactivation by Reduction?

Abstract

The Co(III)-containing water-soluble metalloporphyrin cobalt(III) meso-tetra(4-N-methylpyridyl)porphine pentaiodide (CoIIITMPyP) is a potential cyanide-scavenging agent. The rate of reduction of CoIIITMPyP by ascorbate is facile enough that conversion to the Co(II)-containing CoIITMPyP should occur within minutes at prevailing in vivo levels of the reductant. It follows that any cyanide-decorporating capability of the metalloporphyrin should depend more on the cyanide-binding characteristics of CoIITMPyP than those of the administered form, CoIIITMPyP. Addition of cyanide to buffered aqueous solutions of CoIITMPyP (pH 7.4, 25–37 °C) results in quite rapid (k2 = ~103 M−1 s−1) binding/substitution of cyanide anion in the two available axial positions with high affinity (K′β = 1010 to 1011). Electron paramagnetic resonance spectroscopic measurements and cyclic voltammetry indicate that cyanide induces oxidation to the Co(III)-containing dicyano species. The constraints that these observations put on plausible mechanisms for the reaction of CoIITMPyP with cyanide are discussed. Experiments in which CoIIITMPyP and cyanide were added to freshly drawn mouse blood showed the same sequence of reactions (metalloporphyrin reduction → cyanide binding/substitution → reoxidation) to occur. Therefore, in cyanide-scavenging applications with this metalloporphyrin, we should be taking advantage of both the improved rate of ligand substitution at Co(II) compared to that at Co(III) and the increased affinity of Co(III) for anionic ligands compared to that of Co(II). Finally, using an established sublethal mouse model for cyanide intoxication, CoIIITMPyP, administered either 5 min before (prophylaxis) or 1 min after the toxicant, is shown to have very significant antidotal capability. Possible explanations for the results of a previous contradictory study, which failed to find any prophylactic effect of CoIIITMPyP toward cyanide intoxication, are considered.

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

“…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.…”

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

“…Therefore, even if the complex is given as Co(III)N 4 [11.3.1], it is to be anticipated that it will become reduced to Co(II)N 4 [11.3.1] in vivo , as we have recently shown to be the case for the metalloporphyrin CoTMPyP system. 11,33 Therefore, if CoN 4 [11.3.1] is to be used as an antidote to cyanide toxicity, then its ability to bind cyanide in the reduced form is of paramount importance. The current results (Figures 2A and 5), however, lead us to conclude that cyanide rapidly catalyzes the conversion of the reduced complex to the oxidized form, Co(III)N 4 [11.3.1]-(CN − ) 2 .…”

“…Again, this is reminiscent of CoTMPyP, where the oxidizing equivalents appear to be provided by protons with evolution of hydrogen. 11,33 Titrations using a cyanide-selective electrode (Figure 1) and a spectrophotometric approach (Figure 2B) show that two cyanide molecules bind per Co(II)N 4 [11.3.1] cation and that the overall binding constant is 2.7 (±0.2) × 10 5 . In summary, as a cyanide-scavenging system, CoN 4 [11.3.1] appears to function via a redox-dependent mechanism, which takes advantage of (i) the typically facile nature of ligand substitution by Co(II) compared to that by Co(III) 35,36 coupled to (ii) the improved stability of anion binding to a trivalent metal ion and (iii) the relatively substitution inert behavior of Co(III) complexes, which prevents the reversal of the process and release of any cyanide once bound.…”

“…We have very recently shown that a Co(III)-containing water-soluble porphyrin, exhibiting slightly better cyanide-binding capability than Cbi, functions as a cyanide antidote in mice. 10,11 Consequently, it appears that many compounds in which cobalt(III) is surrounded by a square-planar arrangement of nitrogen donors with two labile ligands in the axial positions are good candidate cyanide antidotes. Some known metalloporphyrins, including the one we have studied, are certainly easier to synthesize and therefore cheaper to produce than corrinoids like Cbl and Cbi.…”

Reaction Kinetics of Cyanide Binding to a Cobalt Schiff-Base Macrocycle Relevant to Its Mechanism of Antidotal Action

“…8,15,16 Quite recently, however, our group has suggested that the trans-effect argument is probably moot, because while cobaltbased cyanide antidotes may be administered in Co(III) forms, all the ones we have examined thus far are quickly reduced to predominantly Co(II) forms in vivo. 5,17,18 Unlike their Co(III) counterparts, Co(II) complexes are substitution labile and, therefore, able to rapidly bind any cyanide present without assistance from trans effects (or cis effects). Conveniently, the Co(II)-cyanide adducts seem to have redox potentials favoring re-oxidation to Co(III) forms, 17 retaining two bound (i.e., detoxified) cyanide anions in what are now substitution-inert complexes that may be excreted.…”