2-Amino-9H-pyrido [2, 3-b] indole (AαC) is the most abundant heterocyclic aromatic amine and a possible liver and gastrointestinal carcinogen found in the mainstream tobacco smoke. The amount of AαC arises in a single cigarette smoke is 25 to 100 times higher than one of the thoroughly investigated group 1 human carcinogen 4-aminobiphenyl. Upon metabolic activation, AαC forms the covalent adduct at the C8-position of 2'-deoxyguanosine. We report here the total synthesis of oligonucleotides containing 2'-dGuo-C8-AαC adduct. In our approach, 2-chloroindole-3-carboxaldehyde served as a precursor of 9-benzyl-9H- pyrido [2, 3-b] indol-2-amine which was subjected to Buchwald Hartwig cross coupling with protected C8-bromo-2'-deoxyguanosine derivative to furnish the 2'-dGuo-C8-AαC adduct. Deprotection followed by conversion to the corresponding phosphoramidite of this C8-dGuo adduct provided the monomer for solid-phase DNA synthesis, which was used to generate the site-specific oligonucleotides, the substrates for investigating the biological outcome of this adduct.

Synthesis of oligonucleotides containing C8-2'-deoxyguanosine adduct of the tobacco carcinogen 2-amino-9H-pyrido [2, 3-b] indole (AαC)

253rd National Meeting (2017)

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