The general goal of Project 1 is to develop flexible and practical methods for synthesis of deoxyoligonucleotides to which carcinogens have been attached in a structurally defined manner. The project will play a pivotal role in the Program Project, i.e., it will provide DNA oligomers containing adducts of important carcinogens for use in biophysical and biochemical studies. Specific goals to be addressed involve preparation of adducts of polycyclic aromatic hydrocarbons (PAH) at exocyclic amino sites on guanine and adenine in oligodeoxynucleotides. Adducts of the PAH diol epoxides derived from benzo[a]pyrene, benzo[c]phenanthrene, benz[a]anthracene, and 7,12-dimethylbenz[a]anthracene will be prepared. Two novel, indirect strategies will be employed for the synthesis of these adducted oligomers. One will involve differential protection of potentially nucleophilic sites on the oligomer followed by (1) selective deprotection of the target site and then (2) reaction with the diol epoxide as a solution to the regiospecificity problem that plagues direct adduction strategies. The other will involve halogen-substituted nucleosides which will be incorporated into oligomers; adducts will be formed in a completely regiospecific and sterospecific manner via displacement of the halogen by aminotriols derived from the PAH diol epoxides.
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