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Chemical characteristics of the imidazole moiety of deoxyguanosine

脱氧鸟苷咪唑部分的化学特性

基本信息

批准号：
09672150
负责人：
KOHDA Kohfuku
金额：
$ 1.98万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Carcinogens such as arylamines and nitroarens generate mainly C8-arylaminodeoxyguanosine adduct in DNA when they were treated to cells. For the formation of the adduct, a possible mechanism that N7-arylaminodeoxyguanosine is an intermediate was proposed. In order to clear the mechanisms, we used a series of 1-methylbenzimidazole derivatives as models of the imidazole moiety of deoxyguanosine, and intended to synthesize a series of 1-methyl-3-phenylaminobenzimidazoles, the equivalent products of N7-phenylaminodeoxyguanosinium salt. Chemical characteristics of 1-methyl-3-phenylaminobenzimidazoles were also examined. Syntheses of 1-methyl-3-phenylaminobenzimidazoles are as follows. 4-Substituted (CHィイD23ィエD2, H, F, CFィイD23ィエD2, or NOィイD22ィエD2)-2-aminobenzanilide was allowed to react with nitrosobenzene and subsequent removal of the benzoyl group gave 4-substituted-2-phenylazoaniline. This compound was allowed to react with formic acid to give 5-substituted-1-methylbenzimidazoles. Methylation of this compound with MeI proceeded selectively at the N of another side and formed the desired 5-substituted-1-methyl-3-phenylaminobenzimidazolium salts (BI). Heating BI in MeOH/HィイD22ィエD2O produced 5-substituted-1-methyl-2-oxobenzimidazole only in the case of BI with a strongly electron-withdrawing substituent, CFィイD23ィエD2 and NOィイD22ィエD2. alkaline treatment of BI produced 4-substituted-NィイD11ィエD1-methyl-2-phenylazoaniline derivatives in all cases. For comparison between the amino and phenylamino groups, 3-(amino and phenylamino)-1-methyl-5-trifluorobenzimidazoles were used and their reactivity was studied. It was found that phenylamino derivative was more reactive. On the other hand, 7-aminoguanosine is so reactive and formed 2-oxoguanosine so easily. These results suggested that the chemical reactivity of benzimidazole skeleton is quite different from that of benzimidazole.

芳香胺和硝基芳烃等致癌物作用于细胞时，主要在DNA中生成C8-芳香氨基脱氧鸟苷加合物。对于加合物的形成，提出了一个可能的机制，N7-芳氨基脱氧鸟苷是一个中间体。为了阐明其作用机理，我们以一系列1-甲基苯并咪唑衍生物作为脱氧鸟苷咪唑部分的模型化合物，拟合成一系列1-甲基-3-苯胺基苯并咪唑类化合物，即N7-苯胺基脱氧鸟苷盐的等价物。对1-甲基-3-苯胺基苯并咪唑类化合物的化学性质进行了研究。1-甲基-3-苯基氨基苯并咪唑的合成如下。4-使取代的（CH_（CN）D23_（CN）D23_（CN）D2，H，F，CF_（CN）D23_（CN）D2，或NO_（CN）D22_（CN）D2）-2-氨基苯甲酰苯胺与亚硝基苯反应，随后除去苯甲酰基，得到4-取代的-2-苯基偶氮苯胺。使该化合物与甲酸反应，得到5-取代的-1-甲基苯并咪唑。该化合物与MeI在另一侧的N上选择性地进行甲基化，并形成所需的5-取代-1-甲基-3-苯基氨基苯并咪唑盐（BI）。在MeOH/H2O中加热BI仅在BI具有强吸电子取代基的情况下产生5-取代的-1-甲基-2-氧代苯并咪唑，CF取代D23取代D2和NO取代D22取代D2。在所有情况下，BI的碱处理产生4-取代的-N-甲基-D11-N-甲基-D1-甲基-2-苯基偶氮苯胺衍生物。为了比较氨基和苯基氨基，使用3-（氨基和苯基氨基）-1-甲基-5-三氟苯并咪唑并研究它们的反应性。发现苯胺基衍生物的反应活性更高。另一方面，7-氨基鸟苷是如此的反应性，并且如此容易形成2-氧代鸟苷。这些结果表明，苯并咪唑骨架的化学反应性与苯并咪唑有很大的不同。