EXOCYCLIC DNA ADDUCTS--SYNTHETIC AND ANALYTIC STUDIES

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DESCRIPTION: (Applicant's Description) The organic, synthetic, and analytical chemistry described in this section of the program is designed to support biological and physico-chemical studies in the accompanying projects. The primary goal is to provide modified 2'-deoxynucleosides derivatized in the form of their DMT-phosphoramidites (N-protected where necessary) for synthetic DNA oligomers. The modified nucleosides comprise three groups: (a) those that represent or mimic damage induced in DNA by electrophiles or by reactive oxidizing species, (b) those that are non-hydrolysable mimics of the normal natural substrates for studies of DNA repair enzymes, and those that after activation will form exocyclic adducts or inter-strand crosslinks. Two main themes dominate the synthetic chemistry. The first involves having a vicinal glycol in a nucleoside side-chain that by periodate oxidation can be converted to an aldehyde. The latter will generate the desired adducted base, post-synthetically. Adducts related to araldehyde, crotonaldehyde, lipid peroxidation adducts, the natural abasic site, and ribonolactone will be synthesized in situ by this method. Cross-links also will be generated by this approach. The second theme concerns the use of "carba" purines and pyrimidines as stable or non-hydrolysable mimics of both normal bases and oxidized or adducted forms of endogenous DNA damage. These will be used: (a) in studies involving mechanisms by which DNA repair enzymes such as MutY operate, including the eversion (flip-out) process, (b) for studies of mutagenic mechanisms, and (c) to obtain crystal structures of complexes with DNA repair enzymes.