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Cobalt(III) Macrocycles as Possible Cyanide Antidotes

Benz, Oscar (2013) Cobalt(III) Macrocycles as Possible Cyanide Antidotes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Several cobalt-containing macrocyclic compounds have been examined for their ability to bind cyanide rapidly with a large association constant. These macrocycles were synthesized and studied, resulting in one in particular (Cobalt(III) meso-tetra(4-N-methylpyridyl)porphine(Co(III)TMPyP)) having the physical characteristics necessary for potential use as a cyanide antidote. The binding of cyanide to the oxidized form, forming Co(III)TMPyP(CN)2, at pH 7.4, 25°C, has been shown to be completely cooperative (αH = 2) with an association constant of 2.1 ± 0.2 x 1011. The kinetics were investigated by stopped-flow spectrophotometry and revealed a complicated net reaction exhibiting four phases at pH 7.4 under conditions where cyanide was in excess. The data suggest molecular HCN (rather than CN-) to be the attacking nucleophile around neutrality. Additionally, the administration of Co(III)TMPyP one minute after a lethal dose of cyanide to mice resulted in a marked increase in survival (67%) compared to controls (33%). The time required for the Co(III)TMPyP-treated mice to right themselves from a supine position was also significantly decreased (9 ± 2 min.) compared to the controls (33 ± 2 min.).
Since blood contains ascorbate, the rate of reduction of Co(III)TMPyP by ascorbate is of interest. Indeed, the rate of reduction of Co(III)TMPyP by ascorbate is fast, with second order rate constants of 8.3 x 104 M-1s-1 at 25°C and 1.4 x 105 M-1s-1 at 37°C. Addition of cyanide to Co(II)TMPyP results in the binding of cyanide as evidenced by electric paramagnetic resonance spectroscopy but cyclic voltammetry and kinetic investigations indicate that cyanide induces oxidation to the Co(III) dicyano species. The equilibrium binding constant derived from the addition of cyanide to the reduced form was found to be 2.1 ± 0.1 x 1010 (Kβ), at pH 7.4, 25°C. Electron paramagnetic resonance spectra of mouse blood taken after the addition of the Co(III)TMPyP show that the cobalt is reduced and that subsequent addition of cyanide to the blood results in the disappearance of this signal indicating that cyanide scavenging has taken place. The kinetics of cyanide binding to Co(II)TMPyP are complicated; four phases were found, which were shown to be dependent on the cyanide concentration. A mechanism for the binding of cyanide to the reduced form is proposed.
With regard to public health, HCN is a known toxic component of modern fires and smoke inhalation victims are probably the most frequent patients exhibiting symptoms of acute cyanide toxicity presenting at emergency rooms in Europe and the U.S. Furthermore, there is a paucity of effective cyanide antidotes at present. As such, the development of efficacious cyanide antidotes is desirable.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Benz, Oscarosb1@pitt.eduOSB1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBarchowsky, Aaronaab20@pitt.eduAAB20
Committee CoChairPeterson, Jamesjpp16@pitt.eduJPP16
Committee MemberPearce, Lindalip10@pitt.eduLIP10
Committee MemberPitt, Brucebrucep@pitt.eduBRUCEP
Committee MemberStoyanovsky, Detchodas11@pitt.eduDAS11
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberGil, Robertorgil@andrew.cmu.edu
Date: 29 January 2013
Date Type: Completion
Defense Date: 20 November 2012
Approval Date: 29 January 2013
Submission Date: 26 November 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 97
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Doctoral Dissertation
Date Deposited: 29 Jan 2013 22:21
Last Modified: 15 Nov 2016 14:07
URI: http://d-scholarship.pitt.edu/id/eprint/16760

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