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
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- 作者：Takeji Takamura-Enya ; Satoko Ishikawa ; Masataka Mochizuki ; and Keiji Wakabayashi
- 刊名：Chemical Research in Toxicology
- 出版年：2006
- 出版时间：June 2006
- 年：2006
- 卷：19
- 期：6
- 页码：770 - 778
- 全文大小：147K
- 年卷期：v.19,no.6(June 2006)
- ISSN：1520-5010
文摘
Synthesis of 2'-deoxyguanosine-C8 adducts (dG-C8 adducts) with mutagenic/carcinogenic heterocyclicamines (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 obtainedderivatives 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 thearylamination reaction. Subsequent deprotection of the resulting dG-C8 adduct derivatives yieldedauthentic samples of dG-C8 adducts with HCAs. The dG-C8-PhIP adduct was further converted intoa suitably protected phosphoramidite derivative for automated DNA synthesis. Synthesis of oligonucleotideswherein PhIP adducted on each G within a triple G sequence in codon 869 (TCC GGG AAC) of rat Apcgenes was performed with a modification in the coupling time and deprotection procedures.
C, we obtainedderivatives 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 thearylamination reaction. Subsequent deprotection of the resulting dG-C8 adduct derivatives yieldedauthentic samples of dG-C8 adducts with HCAs. The dG-C8-PhIP adduct was further converted intoa suitably protected phosphoramidite derivative for automated DNA synthesis. Synthesis of oligonucleotideswherein PhIP adducted on each G within a triple G sequence in codon 869 (TCC GGG AAC) of rat Apcgenes was performed with a modification in the coupling time and deprotection procedures.