This project aims to elucidate the mechanisms by which DNA strand cleavage occurs following hydrogen atom abstraction from the sugar phosphate backbone by the activated forms of the antitumor antibiotics calicheamicin, esperamicin, dynamicin, neocarzinostatin, bleomycin, and by hydroxyl radicals in radiation chemotherapy. The mechanisms for the generation of sugar radicals in the sugar phosphate backbone are well understood but the ensuing chemistry of these beta-phosphatoxyalkyl radicals, with the exception of the bleomycin case, has not been extensively investigated. The investigation will focus on this aspect of the mechanism, in the course of which the actual strand cleavage occurs. The free radical chemistry of beta-phosphatoxyalkyl radicals will be studied with a series of simple model compounds and the fundamental mechanisms by which such species rearrange, and suffer carbon-carbon bond cleavage in the presence of oxygen, determined. A series of more complex nucleotide based models will then be synthesized which will enable the controlled and unambiguous generation of C-4' radicals and C-4' peroxyl radicals. These models will be studied first as the monomers and subsequently in di- and trinucleotides and the degradation products isolated and characterized. A range of analytical techniques including 1H and 31P-NMR spectroscopy, mass spectrometry, ESR spectroscopy, and HPLC will be used both to monitor reactions and analyze products. An increased understanding of the mechanisms of DNA cleavage by free radicals will be the result of this study. This will ultimately assist in the rational design of improved cancer chemotherapies.
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