Reactive intermediate-mediated free radical

Many chemicals form reactive, electrophilic intermediates and free radicals during their metabolism in the body. These can be formed via enzyme-mediated reactions (many of which are oxidations) or from autoxidation of small molecules like flavins and thiols. These electrophilic intermediates covalently react with nucleophilic sites in the cell, including glutathione (GSH) and thiol-containing proteins, causing cellular... 

The reaction of peroxynitrite with the biologically ubiquitous C02 is of special interest due to the presence of both compounds in living organisms therefore, we may be confident that this process takes place under in vivo conditions. After the discovery of this reaction in 1995 by Lymar [136], the interaction of peroxynitrite with carbon dioxide and the reactions of the formed adduct nitrosoperoxocarboxylate ONOOCOO has been thoroughly studied. In 1996, Lymar et al. [137] have shown that this adduct is more reactive than peroxynitrite in the reaction with tyrosine, forming similar to peroxynitrite dityrosine and 3-nitrotyrosine. Experimental data were in quantitative agreement with free radical-mediated mechanism yielding tyrosyl and nitric dioxide radicals as intermediates and were inconsistent with electrophilic mechanism. The lifetime of ONOOCOO was estimated as <3 ms, and the rate constant of Reaction (42) k42 = 2 x 103 1 mol 1 s 1. 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

This review focuses on free radical-mediated stereoselective bond construction in which the carbonyl group plays a key role. Reaction at the carbonyl group as well as on carbons alpha and beta are described. The general reaction characteristics of these reactive intermediates are as follows. The acyl radicals are nucleophilic in character and thus they react easily with electrophilic acceptors. On the other hand, radicals on carbon alpha to the carbonyl are electrophilic in nature and their reactivity matches with nucleophilic partners. The majority of reactions at carbon beta to the carbonyl are in a, -unsaturated systems and in these the beta carbon is electrophilic. 

The reactivity of water with both carbanion and carbocation intermediates is well known and recognised, but until recently it was generally believed that water is inert towards free radicals. Some years ago, Cuerva et al. by chance observed that tertiary radicals were reduced effectively in the presence of bis(cyclopentadienyl)titanium(III) chloride and water. Now the authors have solid evidence to show that water really acts as a complete hydrogen atom source rather than a simple proton donor for radical reductions mediated by Ti(III) and, presumably, other metals that react by single electron transfer (Scheme 8.7).6... 

Human alveolar epitheUal cells exposed to residual oil fly ash release inflanunatory cytokines including IL-6, IL-8, and tumour necrosis factor (Carter et al. 1997). The IL-6 response was inhibited by the metal chelator deferoxamine and the free radical scavenger N-acetyl-L-cysteine, suggesting that the activation of NFxB may be mediated through reactive oxygen intermediates generated by transition metals found in residual oil fly ash (Quay et al. 1998). 

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