Peroxynitrite metal complexes

Although hydroxyl radical is commonly assumed to be the most toxic of the oxygen radicals (with little direct evidence), other direct reactions are more likely to be important for understanding the cytotoxicity of peroxynitrite. A second oxidative pathway involves the heterolytic cleavage of peroxynitrite to form a nitronium-like species (N02 ), which is catalyzed hy transition metals (Beckman et al., 1992). Low molecular weight metal complexes as well as metals bound in superoxide dismutase and other proteins catalyze the nitration of a wide range of phenolics, including tyrosine residues in most proteins (Beckman et al., 1992). 

The decay of LMOONO, generated either as in Eq. (36), or by substitution of peroxynitrite into a metal complex, is usually written as a homolytic process of Scheme 9. The LMO and N02 so generated can then either diffuse apart or recombine within the solvent cage to either regenerate the peroxynitrito complex or form the metal-nitrato intermediate, followed by release of free nitrate by hydrolysis. At the time we initiated the work described below, there were no clear examples of LMOONO species isomerizing to a metal nitrato complex, although such reactions have been considered as a possibility (180-182). 

The cadmium(II) complex corresponding to 9 (M = Cd n = 2) was the first texaphyrin made [6], This aromatic expanded porphyrin was found to differ substantially from various porphyrin complexes and it was noted that its spectral and photophysical properties were such that it might prove useful as a PDT agent. However, it was also appreciated that the poor aqueous solubility and inherent toxicity of this particular metal complex would likely preclude its use in vivo [29-31], Nonetheless, the coordination chemistry of texaphyrins such as 9 was soon generalized to allow for the coordination of late first row transition metal (Mn(II), Co(II), Ni(II), Zn (II), Fe(III)) and trivalent lanthanide cations [26], This, in turn, opened up several possibilities for rational drag development. For instance, the Mn(II) texaphyrin complex was found to act as a peroxynitrite decomposition catalyst [32] and is being studied currently for possible use in treating amyotrophic lateral sclerosis. This work, which is outside the scope of this review, has recently been summarized by Crow [33],... 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

It was shown that tryptophan is also nitrated by peroxynitrite in the absence of transition metals to one predominant isomer of nitrotryptophan, as determined from spectral characteristics and liquid chromatography-mass spectrometry analysis. Typical hydroxyl radical scavengers partially inhibited the nitration" . The yields of the nitration of tyrosine and salicylate by peroxynitrite are significantly improved by the Fe(III)-EDTA complex " ". ... 

In another class of reactions, NO is oxidized to N03 or its equivalent by metal-(02/02 ) complexes. In these reactions, NO first adds to the 02 moiety to form a peroxynitrito intermediate that can decompose in various ways.203 The analogy with the direct reaction of NO with free superoxide to form peroxynitrite and its isomerization to nitrate is clear. An important example is the oxidation of NO to NO3 by oxyhemoglobins, where the Fe-02 reactants have considerable Fem-(02 ) character.204 In other examples, NO reacts with superoxo complexes of Rh(III) and Cr(III) to produce peroxonitrito intermediates that decompose in complicated ways.205,206... 

NO donors may play some role as novel cancer therapeutics when used alone or with existing cancer chemotherapy agents (Huerta et al. 2008). NO donors available or in development include organic nitrates, metal-NO complexes, 5-nitrosothiols, sydnonimines (which produce both NO and superoxide, and hence peroxynitrite), diazeniumdiolates ( NONOates ), and certain NO-hybrids (NO linked to active drugs of other classes) (Huerta et al. 2008). Examples of NO-hybrids include NO-aspirin, other NO-nonsteroidal anti-inflammatory drugs, and NO-statins. 

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