Reaction of N-hydroxylamine and N-acetoxy derivatives of 2-amino-3-methylimidazolo[4,5-f]quinoline with DNA. Synthesis and identification of N-(deoxyguanosin-8-yl)-IQ.
Reaction of N-hydroxylamine and N-acetoxy derivatives of 2-amino-3-methylimidazolo[4,5-f]quinoline with DNA. Synthesis and identification of N-(deoxyguanosin-8-yl)-IQ.
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2-氨基-3-甲基咪唑并[4,5-f]喹啉的 N-羟胺和 N-乙酰氧基衍生物与 DNA 的反应。
DOI：
10.1093/carcin/9.6.1061
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发表时间：
1988
期刊：
影响因子：
4.7
通讯作者：
S. Thorgeirsson
中科院分区：
文献类型：
--
作者：
E. Snyderwine;P. Roller;R. Adamson;S. Sato;S. Thorgeirsson
致癌物2-氨基-3-甲基咪唑并[4，5-f]喹啉（IQ）的N-羟胺在pH 7时与小牛胸腺DNA共价结合，在酸性条件（pH 5）下结合率高11%。在中性pH下，N-羟基-IQ与单链多核苷酸结合的程度按以下顺序：聚鸟苷酸远大于聚腺苷酸大于聚胞苷酸=聚尿苷酸。在中性pH条件下，致癌物与DNA、聚鸟苷酸和聚腺苷酸的结合分别增强了6倍、4倍和2倍，推测N-羟基-IQ和乙酸酐原位生成N-乙酰氧基-IQ。在pH 7条件下，N-乙酰氧基-IQ（与N-羟基-IQ和乙酸酐原位生成）与脱氧鸟苷反应，合成了N-（脱氧鸟苷-8-基）-IQ，其结构经NMR、质谱和紫外吸收光谱表征。已与N-羟基-IQ在体外反应的酶促水解的DNA的反相HPLC显示主要加合物，其在色谱上与合成的N-（脱氧鸟苷-8-基）-IQ相同。此外，N-乙酰氧基-IQ，化学生成的乙酸酐或酶与哺乳动物乙酰转移酶，形成一个主要的加合物与DNA，这是色谱相同的合成N-（脱氧鸟苷-8-基）-IQ。结果表明，N-羟基-IQ和N-乙酰氧基-IQ与DNA反应主要形成N-（脱氧鸟苷-8-基）-IQ加合物。
The N-hydroxylamine of the carcinogen 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) covalently bound to calf thymus DNA at pH 7, and the binding was 11% higher under acidic conditions (pH 5). The extent of N-hydroxy-IQ binding to single-stranded polynucleotides at neutral pH was in the following order: polyguanylic acid much greater than polyadenylic acid greater than polycytidylic acid = polyuridylic acid. The binding of the carcinogen to DNA, polyguanylic acid and polyadenylic acid at neutral pH was enhanced 6-, 4- and 2-fold respectively by the presumed in situ formation of N-acetoxy-IQ from N-hydroxy-IQ and acetic anhydride. N-(Deoxyguanosin-8-yl)-IQ was synthesized by reaction at pH 7 of N-acetoxy-IQ (formed in situ with N-hydroxy-IQ and acetic anhydride) with deoxyguanosine and the structure characterized by NMR, mass spectral and UV absorption spectral analyses. Reverse phase HPLC of enzymatically hydrolyzed DNA which had been reacted with N-hydroxy-IQ in vitro showed a major adduct which was chromatographically identical to synthetic N-(deoxyguanosin-8-yl)-IQ. In addition, N-acetoxy-IQ, generated chemically by acetic anhydride or enzymatically with mammalian acetyltransferase, formed one major adduct with DNA which was chromatographically identical to the synthetic N-(deoxyguanosin-8-yl)-IQ. The results indicate that N-hydroxy-IQ and N-acetoxy-IQ react with DNA forming primarily the N-(deoxyguanosin-8-yl)-IQ adduct.