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Amination of nucleic acid bases-A basic study on the reaction mechanism of aminating carcinogens

核酸碱基胺化——胺化致癌物反应机理的基础研究

基本信息

批准号：
62570947
负责人：
KOHDA Kohfuku
金额：
$ 1.15万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1988
项目状态：
已结题

项目摘要

Arylnitrenium ion, a reactive intermediate of genotoxic arylhydroxylamine, is considered to modify cellular DNA. However, its reaction mechanism is not clear. This study was carried out in order to obtain a basic knowledge of amination reaction of nucleic acid bases. Hydroxylamine-O-sulfonic acid (HAOS) and 2, 4-dinitrophenoxyamine (DNPA) were used as models of activated genotoxic arylhydroxylamines.1) Aminations of guanosine (GUO) and deoxyguanosine (dG) with HAOS or DNPA gave various products depending on the reaction condition. Amination of Guo with DNPA in DMF gave 7-amino-Guo, which was readily converted to 8, 5'-O-cyclo-Guo and 8-hydroxy-Guo. dG gave only deglycosylated 7-amino-guanine under the same reaction condition. Amination of Guo and dG with HAOS at above pH 9 gave the corresponding 1-amino derivatives, whereas those in acidic media at pH 2-4 gave 8-amino-Guo and 7-amino-G as the main products, respectively. The mechanism of 8-amino-Guo formation became apparent; 7-NH_2-Guo 7-NH_2-8-NHOH-Guo 8-NHON-Guo 8-NH_2-Guo. 2) Although positional isomers of ring-nitrogen methylated guanines and hydroxylated guanines are known, ring-nitrogen aminated guanines have not been reported. Then, we challenged to the synthesis of all N-aminoguanine isomers. Using dG and O^6-methylguanine (as substrates) and DNPA and HAOS (as reagents), we succeeded in the syntheses of 1-amino-, 3-amino-, 7-amino-, and 9-aminoguanines. Further, diaminoguanines, 1, 7-diamino- and 3, 7- diaminoguanines, were also synthesized.

芳基氮鎓离子是具有遗传毒性的芳基羟胺的活性中间体，被认为可以修饰细胞DNA。但其反应机理尚不清楚。本研究旨在对核酸碱基的胺化反应有一个基本的认识。以羟胺-O-磺酸（HAOS）和2，4-二硝基苯氧基胺（DNPA）为模型化合物，研究了它们对鸟苷（GUO）和脱氧鸟苷（dG）的胺化反应。在DMF中用DNPA胺化Guo得到7-氨基-Guo，其容易地转化为8，5 ′-O-环-Guo和8-羟基-Guo。dG在相同的反应条件下只得到去糖基化的7-氨基鸟嘌呤。Guo和dG与HAOS在pH 9以上的胺化反应得到相应的1-氨基衍生物，而在pH 2-4的酸性介质中则分别得到8-氨基-Guo和7-氨基-G作为主要产物。7-NH_2-Guo 7-NH_2-8-NHOH-Guo 8-NHON-Guo 8-NH_2-Guo。2)尽管已知环氮甲基化鸟嘌呤和羟基化鸟嘌呤的位置异构体，但环氮胺化鸟嘌呤尚未报道。然后，我们挑战所有N-氨基鸟嘌呤异构体的合成。以dG和O^6-甲基鸟嘌呤为底物，DNPA和HAOS为试剂，成功地合成了1-氨基-、3-氨基-、7-氨基-和9-氨基鸟嘌呤。此外，还合成了二氨基鸟嘌呤，1，7-二氨基-和3，7-二氨基鸟嘌呤。