We propose to investigate the synthesis, radical trapping efficacy, diagnostic utility, neuroprotective activity, and mechanistic aspects of a series of new azulenyl nitrones that are structurally related to the novel chromotropic nitrone spin trap 5 (AZN), the first representative of this class first prepared in our laboratory in 1995. These studies will focus on the assessment of whether the designed target molecules 1-4 can be readily synthesized and exhibit improved or complementary behavior compared to other nitrone spin traps previously investigated for the aforementioned biomedical applications. All of the test compounds are azulene derivatives containing either a nitrone moiety at C-1 or vinylogous congeners thereof. The radical trapping efficacy of the test compounds will be gauged by measuring the inhibition of peroxyl radical mediated autoxidation of cumene and by direct competition with the conventional nitrone spin traps PBN and S- PBN. The development of an assay for radical driven oxidative stress in aqueous systems will be pursued with compound 4. Neuroprotective activity of the test compounds will be determined in a murine model of Parkinson's disease employing the neurotoxin MPTP. The possibility of the operation of a catalytic cycle in the biological sequestration of hydroxyl radicals by nitrones will be explored in mechanistic studies employing the stable radical cation derived from azulenyl nitrone 6. This multidisciplinary program will benefit from the input of several consultants whose principal research activities rely on the proposed techniques. Preliminary results obtained with AZN support the principal thesis of this proposal, namely that azulenyl nitrones constitute an important new class of spin trapping agents with promising diagnostic and therapeutic potential.
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