Hypochlorite-Mediated Fragmentation of Hyaluronan, Chondroitin Sulfates, and Related<i>N</i>-Acetyl Glycosamines:  Evidence for Chloramide Intermediates, Free Radical Transfer Reactions, and Site-Specific Fragmentation

Rees, Martin D.; Hawkins, Clare L.; Davies, Michael J.

doi:10.1021/ja0370591

Cited by 92 publications

(133 citation statements)

References 76 publications

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“…Similar spectra were also observed for the oxidation of DMF by hydroxyl radicals ( [45] and by sulphate anion radicals [46]. It seems clear therefore that the same assignments attributable to carboncentred free radicals can be made in the current study on HACl and HepCl, providing support for the 1,2 hydrogen shift mechanism proposed by Davies and co-workers [19] as shown in reaction 8 and in more detail in Scheme 2 in which a chloride ion is eliminated by one-electron reductants to form a nitrogen-centred radical in the first instance followed by rapid re-arangement to form a C-2 radical on the glucosamine moiety. Both EPR data and ion-exchange chromatography to detect chloride in the one-electron reduction of glycosaminoglycan chloramides as well as in pulse radiolysis studies of the reaction of the hydrated electron with chloramines and amides confirm that chloride ion is produced in yields of 100% [47,63].…”

Section: Reduction By the Hydrated Electronsupporting

confidence: 87%

“…Similar site-selective fragmentation was also observed when glycosaminoglycan chloramides (formed through reaction with hypochlorite) were reduced by copper (I) ions and superoxide anion radicals [19,20].…”

Section: Introductionmentioning

confidence: 64%

“…Abstraction of the chlorine atom from N-Cl ,for example, would lead to an Ncentred radical which would, at least in part, re-arrange rapidly to produce the C-2 radical on the glucosamine moiety, as in Scheme 2 or in part to produce C-4 radicals on the uronic acid moiety [19]. These radicals would react rapidly in the presence of oxygen to produce peroxyl radicals.…”

Section: Oxidation By Carbonate Radicalsmentioning

confidence: 99%

“…These radicals would react rapidly in the presence of oxygen to produce peroxyl radicals. The various routes to fragmentation of glycosaminoglycan chloramides via peroxy radical intermediates have been discussed in detail by Rees et al, [19].…”

Section: Oxidation By Carbonate Radicalsmentioning

confidence: 99%

“…Chloramides are weak oxidising agents and are therefore, potential biological targets for reducing radicals and other reducing agents. Indeed, it has been shown that superoxide radicals cause the fragmentation of HA via a metal ion-catalysed reaction with its chloramide derivative [19].…”

Section: Introductionmentioning

confidence: 99%

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One-electron oxidation and reduction of glycosaminoglycan chloramides: A kinetic study

Sibanda

Parsons

Houée-Levin⊥

et al. 2013

Free Radical Biology and Medicine

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Hypochlorous acid and its acid-base counterpart, hypochlorite ions, produced in inflammatory conditions, may produce chloramides of glycosaminoglycans, the latter being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans.The N-Cl group in the chloramides is a potential selective target for both reducing and oxidising radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. In this study,the fast reaction techniques of pulse radiolysis and nanosecond laser flash photolysis have been used to generate both oxidizing and reducing radicals to react with the chloramides of hyaluronan (HACl) and heparin (HepCl).The strong reducing formate radicals and hydrated electrons were found to react rapidly with both HACl and HepCl with rate constants of (1-1.7) x 10 8 M -1 s -1 and (0.7-1.2) x 10 8 M -1 s -1 for formate radicals and 2.2 x 10 9 M -1 s and 7.2 x 10 8 M -1 s -1 for hydrated electrons, respectively. The spectral characteristics of the products of these reactions were identical and were consistent with initial attack at the N-Cl groups, followed by elimination of chloride ions to produce nitrogencentred radicals, which re-arrange subsequently and rapidly to produce C-2 radicals on the glucosamine moiety supporting an earlier EPR study by Rees et 3 This is the first study therefore to conclusively demonstrate that reducing radicals react rapidly with glycosaminoglycan chloramides in a site-specific attack at the N-Cl groups, probably to produce a 100 % efficient biopolymer fragmentation process. Although less reactive, carbonate radicals, which may be produced in vivo via reactions of peroxynitrite with serum levels of carbon dioxide ,also appear to react in a highly site-specific manner at the N-Cl group. It is not yet known if such site-specific attacks by this important in vivo species lead to a more efficient fragmentation of the biopolymers than would be expected for attack by the stronger oxidising species, the hydroxyl radical. It is clear however that the N-Cl group formed in inflammatory conditions in the extracellular matrix does present a more likely target for both reactive oxygen species and for reducing species than the N-H groups in the parent glycosaminoglycans. Graphical abstract4

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