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

Chem Res Toxicol. 2006 Jun;19(6):770-8. doi: 10.1021/tx050296s.

Abstract

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 (Pd(2)dba(3)) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) with a cesium carbonate (Cs(2)CO(3)) base at a reaction temperature of 100 approximately 120 degrees 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% approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amination
  • Amines / chemistry*
  • Bromine Compounds / chemistry
  • Chromatography, High Pressure Liquid
  • Deoxyguanine Nucleotides / chemistry*
  • Heterocyclic Compounds / chemistry*
  • Imidazoles / chemistry*
  • Molecular Structure
  • Oligonucleotides / chemical synthesis*
  • Oligonucleotides / chemistry
  • Organophosphorus Compounds / chemical synthesis
  • Organophosphorus Compounds / chemistry
  • Solvents
  • Spectrum Analysis

Substances

  • Amines
  • Bromine Compounds
  • Deoxyguanine Nucleotides
  • Heterocyclic Compounds
  • Imidazoles
  • Oligonucleotides
  • Organophosphorus Compounds
  • Solvents
  • phosphoramidite
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine