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

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) × 10(5). 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.

Total Synthesis, Structure, and Biological Activity of Adenosylrhodibalamin, the Non-Natural Rhodium Homologue of Coenzyme B12.

B12 is unique among the vitamins as it is biosynthesized only by certain prokaryotes. The complexity of its synthesis relates to its distinctive cobalt corrin structure, which is essential for B12 biochemistry and renders coenzyme B12 (AdoCbl) so intriguingly suitable for enzymatic radical reactions. However, why is cobalt so fit for its role in B12 -dependent enzymes? To address this question, we considered the substitution of cobalt in AdoCbl with rhodium to generate the rhodium analogue 5'-deoxy-5'-adenosylrhodibalamin (AdoRbl). AdoRbl was prepared by de novo total synthesis involving both biological and chemical steps. AdoRbl was found to be inactive in vivo in microbial bioassays for methionine synthase and acted as an in vitro inhibitor of an AdoCbl-dependent diol dehydratase. Solution NMR studies of AdoRbl revealed a structure similar to that of AdoCbl. However, the crystal structure of AdoRbl revealed a conspicuously better fit of the corrin ligand for Rh(III) than for Co(III) , challenging the current views concerning the evolution of corrins.

Synthesis, Optimization, and Biological Evaluation of Corrinated Conjugates of the GLP-1R Agonist Exendin-4.

Corrination is the conjugation of a corrin ring containing molecule, such as vitamin B12 (B12) or B12 biosynthetic precursor dicyanocobinamide (Cbi), to small molecules, peptides, or proteins with the goal of modifying pharmacology. Recently, a corrinated GLP-1R agonist (GLP-1RA) exendin-4 (Ex4) has been shown in vivo to have reduced penetration into the central nervous system relative to Ex4 alone, producing a glucoregulatory GLP-1RA devoid of anorexia and emesis. The study herein was designed to optimize the lead conjugate for GLP-1R agonism and binding. Two specific conjugation sites were introduced in Ex4, while also utilizing various linkers, so that it was possible to identify Cbi conjugates of Ex4 that exhibit improved binding and agonist activity at the GLP-1R. An optimized conjugate (22), comparable with Ex4, was successfully screened and subsequently assayed for insulin secretion in rat islets and in vivo in shrews for glucoregulatory and emetic behavior, relative to Ex4.

Does catalysis of reductive dechlorination of tetra- and trichloroethylenes by vitamin B12 and corrinoid-based dehalogenases follow an electron transfer mechanism?

Knowing the mechanism by which dangerous organic chloride pollutants, such as tetra- or trichloroethylene, are reductively cleaved is an important task for the establishment of remediation strategies and for a better comprehension of bacterial dehalorespiration by corrinoid-based dehalogenases. On the basis of electrochemical and thermodynamic data, application of outersphere and dissociative electron transfer theories allows the prediction of the pertinent activation/driving force relationships characterizing the electron transfer mechanism. They are validated by application of the redox catalysis method to the reaction with two typical outersphere electron donors. The kinetic gap is more than 11 and 7 orders of magnitude for the dehalogenase and for cobalamin, respectively, showing that the electron transfer mechanism is not operative. Multistep mechanisms in which the chloroethylene molecule enters the cobalt coordination sphere are preferred.