This Program Project interactively uses organic synthesis, structural biology, and molecular biology to elucidate at a molecular level the processes by which bifunctional alkylating adducts degrade DNA replication and repair. Effort will focus on agents in which the two sites of possible nucleophilic attack by the DNA are separated by either two or three carbon atoms. Chlorooxirane, a metabolite of vinyl chloride, is an example of the former and alpha, beta-unsaturated aldehydes, such as acrolein and 4-hydroxynonenal, are examples of the latter. Project I will develop synthetic routes to the various types of adducts that can be formed by these electrophiles and synthetic routes for placing these adducts in DNA in a site-specific manner and with defined regiochemistry and stereochemistry. The chemistry of these adducts will be explored. The project will focus on the distal and proximal hydroxyethano and hydroxypropano adducts of dG, dA and dC. The distal and proximal adducts have contrasting chemistry, structures and biology. The distal adducts are believed to be potent mutagens but they represent challenging experimental targets because of chemical instability. The proximal adducts are hypothesized to revert to acyclic adducts in duplexed DNA and to be a source of DNA-DNA and DNA-protein crosslinks. The structures of these crosslinks will be determined and methods will be developed for preparation of nucleosides and oligonucleotides containing them.
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