Efficient Syntheses of C 8 -Aryl Adducts of Adenine and Guanine Formed by Reaction of Radical Cation Metabolites of Carcinogenic Polycyclic Aromatic Hydrocarbons with DNA Qing Dai, Daiwang Xu, Keunpoong Lim, and Ronald G. Harvey* The Ben May Department for Cancer Research, The UniVersity of Chicago, Chicago, Illinois 60637 rharVey@ben-may.bsd.uchicago.edu ReceiVed March 20, 2007 The synthesis of the C 8 -aryl adducts of adenine and guanine formed by reaction of the radical cation metabolites of carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BP) and dibenzo[def,p]chrysene (DBC), with DNA is reported. The synthetic approach involves in the key step direct reaction of a PAH aldehyde with a di- or triamine precursor of a purine. The method is operationally simple, affords good yields of adducts, and is broad in its scope. The C 8 -aryl adducts of adenine and guanine derived from BP (6-BP-8-Ade and 6-BP-8-Gua) and DBC (10-DBC-8-Ade and 10-DBC-8- Gua) were synthesized in good yields by this method. Analogous C 8 -aryl adenine and guanine derivatives of other PAHs (anthracene, benz[a]anthracene, and chrysene) were also readily prepared via this approach. This method of synthesis is superior to the only method that is currently available. It entails direct reaction of short-lived PAH radical cations (generated electrochemically or chemically) with 2′-deoxyribonucleo- sides or the corresponding purine bases. It provides the adducts in low yields accompanied by complex mixtures of secondary products. An alternative synthesis that involves Pd-catalyzed Suzuki-Miyaura coupling of arylboronic acids with 8-bromopurine nucleosides was also investigated. Although the C 8 - purine adducts of PAHs, such as naphthalene, phenanthrene, pyrene, and chrysene, could be prepared by this method, analogous adducts of carcinogenic PAHs and other structurally related PAHs, e.g., anthracene, benz[a]anthracene, benzo[a]pyrene, and dibenzo[def,p]chrysene, could not be obtained. This difference was shown to be a consequence of the facility of competing hydrolytic deboronation of the corresponding arylboronic acids. Introduction Polycyclic aromatic hydrocarbons (PAHs), some of which are potent carcinogens, are ubiquitous environmental pollutants produced in the combustion of organic matter. 1 They are commonly present in smoke from combustion of fossil fuels, tobacco smoke, and smoked and fried foods. Benzo[a]pyrene (BP) is the most intensively investigated PAH carcinogen, and it has been implicated as a principal cancer-causative agent in cigarette smoke. 2-4 * Address correspondence to this author. Phone: 1-(773) 702-6998. Fax: 1-(773) 702-6260. (1) International Agency for Research on Cancer. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Polynuclear Aromatic Compounds, Part 1, Chemical, EnVironmental and Experimental Data; IARC: Lyon, France, 1983; Vol. 32. (2) International Agency for Research on Cancer. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Tobacco Smoke and InVoluntary Smoking; IARC: Lyon, France, 2004; Vol. 83. (3) Pfiefer, G. P.; Denissenko, M. F.; Olivier, M.; Tretyakova, N.; Hecht, S.; Hainaut, P. Oncogene 2002, 21, 7435-7451. (4) World Health Organization. Tobacco or Health: A Global Status Report; WHO: Geneva, 1997; pp 10-48. 4856 J. Org. Chem. 2007, 72, 4856-4863 10.1021/jo070518m CCC: $37.00 © 2007 American Chemical Society Published on Web 05/27/2007