Chemical Synthesis of 2‘-Deoxyguanosine−C8 Adducts with Heterocyclic Amines:  An Application to Synthesis of Oligonucleotides Site-Specifically Adducted with 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Synthesis of 2‘-deoxyguanosine−C8 adducts (dG−C8 adducts) with mutagenic/carcinogenic heterocyclic amines (HCAs) was achieved via the Buchwald−Hartwig arylamination reaction. By using tris(dibenzylideneacetone)dipalladium (Pd2dba3) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) with a cesium carbonate (Cs2CO3) base at a reaction temperature of 100∼120 °C, we obtained derivatives of dG−C8 adducts with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-6-methyldipyrido[1,2-a:3‘,2‘-d]imidazole (Glu-P-1), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in 69%∼97% yield from the cross-coupling of an 8-bromodeoxyguanosine derivative. In the case of PhIP, it was found that dimethyl sulfoxide (DMSO) was the critical solvent for the arylamination reaction. Subsequent deprotection of the resulting dG−C8 adduct derivatives yielded authentic samples of dG−C8 adducts with HCAs. The dG−C8−PhIP adduct was further converted into a suitably protected phosphoramidite derivative for automated DNA synthesis. Synthesis of oligonucleotides wherein PhIP adducted on each G within a triple G sequence in codon 869 (TCC GGG AAC) of rat Apc genes was performed with a modification in the coupling time and deprotection procedures.