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

Takeji Takamura-Enya, Satoko Ishikawa, Masataka Mochizuki, Keiji Wakabayashi

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 (Pd2dba3) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (xantphos) with a cesium carbonate (Cs 2CO3) 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-methyl-dipyridol [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.

Original languageEnglish
Pages (from-to)770-778
Number of pages9
JournalChemical Research in Toxicology
Volume19
Issue number6
DOIs
Publication statusPublished - 2006 Jun

Fingerprint

Deoxyguanosine
Oligonucleotides
Amines
Derivatives
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline
2-amino-3-methylimidazo(4,5-f)quinoline
2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole
Xanthenes
Carbolines
Quinoxalines
Dimethyl Sulfoxide
Codon
Rats
Genes
Temperature
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
DNA
3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

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title = "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",
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 (Pd2dba3) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (xantphos) with a cesium carbonate (Cs 2CO3) 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-methyl-dipyridol [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.",
author = "Takeji Takamura-Enya and Satoko Ishikawa and Masataka Mochizuki and Keiji Wakabayashi",
year = "2006",
month = "6",
doi = "10.1021/tx050296s",
language = "English",
volume = "19",
pages = "770--778",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
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T1 - Chemical synthesis of 2′-deoxyguanosine-C8 adducts with heterocyclic amines

T2 - An application to synthesis of oligonucleotides site-specifically adducted with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

AU - Takamura-Enya, Takeji

AU - Ishikawa, Satoko

AU - Mochizuki, Masataka

AU - Wakabayashi, Keiji

PY - 2006/6

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N2 - 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 (Cs 2CO3) 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-methyl-dipyridol [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.

AB - 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 (Cs 2CO3) 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-methyl-dipyridol [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.

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