This project is concerned with the development of improved and efficient methodologies for synthesizing model DNA adducts by reacting selected mutagenic polycyclic aromatic diol epoxide compounds with deoxyribooligonucleotides of defined base composition and sequence. The elucidation of the relationships between the structures of this class of chemical carcinogens, the types of DNA adducts formed, and the chemical lesions and damage which they induce in the genetic material of the cell, remain among the most important problems for elucidating the molecular mechanisms by which these compounds induce mutations and cancer. Polynuclear aromatic diol epoxide molecules such as benzo[a]pyrene-7,8-diol -9,10-epoxide (BPDE), benzo[c]phenanthrene-3,4-diol-1,2-epoxide (BcPhDE), and the mono- and dimethyl derivatives of chrysene-1,2-diol-3,4-epoxide (CDE) and benz[a]anthracene-3,4-diol-1,2-epoxide (BADE) form major adducts which involve covalent binding predominantly at N2 of guanine (BPDE and mono-methyl derivatives of CDE), and covalent binding at both N2 of guanine and N6 of adenine (BcPhDE and certain methyl derivatives of CDE and BADE). In addition, other minor adducts in each case are formed, and each of the aromatic diol epoxides can give rise to varying proportions of cis and trans addition products. In this project, efficient protocols for synthesizing the different major and minor adducts of defined chemical composition, stereochemistry, and adduct placement within defined base sequences in oligonucleotides, will be developed. The synthesis protocols, and in some cases the PAH diol epoxide-DNA model adducts, will be made available to researchers for in vitro and in vivo site-directed mutagenesis studies. The availability of such model DNA adducts should provide opportunities for significant advances in this field of chemical carcinogen and mutagen research since chemically well defined DNA adducts will be made available for chemical structure-biological activity correlation experiments.
| Pirogov, N; Shafirovich, V; Kolbanovskiy, A et al. (1998) Role of hydrophobic effects in the reaction of a polynuclear aromatic diol epoxide with oligodeoxynucleotides in aqueous solutions. Chem Res Toxicol 11:381-8 |
| Xu, R; Dwarakanath, S; Cosman, M et al. (1996) Site-specific adducts derived from the binding of anti-5-methylchrysene diol epoxide enantiomers to DNA: synthesis and characteristics. Carcinogenesis 17:2035-42 |
| Mao, B; Li, B; Amin, S et al. (1993) Opposite stereoselective resistance to digestion by phosphodiesterases I and II of benzo[a]pyrene diol epoxide-modified oligonucleotide adducts. Biochemistry 32:11785-93 |
