Rayat Sundeep, Qian Ming, Glaser Rainer
Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
Chem Res Toxicol. 2005 Aug;18(8):1211-8. doi: 10.1021/tx050082a.
A discussion of nitrosative deamination of cytosine 1 is presented that argues for the formation of 6 by diazotization of 1 to cytosinediazonium ion 2 and its electrostatic complex 3, dediazoniation to 4 <--> 5, and amide-bond cleavage to 6. The reaction channels available to 6 include hydrolytic deglycation to 3-isocyanatoacrylonitrile 7, water addition to carbamic acid 9 with the possibility for re-closure to uracil 13, water addition to carbamic acid 9, and decarboxylation to 3-aminoacrylonitrile 10. With a view to the instability of the carbamic acid 9, the carbamate models ethyl (Z)-2-cyanovinylcarbamate 14 and (Z)-2-cyano-1-tert-butylvinylcarbamate 20 were studied. Acid-catalyzed hydrolysis of 14 leads to 2-amino-carbonylphenylcarbamate 15, and its cyclization yields the benzo-fused uracil quinazoline-2,4-dione 16. In contrast to the aromatic system 14, acid-catalyzed cyclization cannot compete with oligomerization in the case of 20, and 5-tert-butyluracil 22 is accessible only with base-catalysis. It is shown that 23, the parent of 10, also easily polymerizes. The experimental results provide a rationale as to why 9, 10, and 12 would have escaped detection in in vitro studies: they would have oligomerized. In contrast to the in vitro experiments, the oligomerizations of 9, 10, or 12 clearly are not relevant in vivo because of low monomer concentrations. With the exclusion of recyclization and of oligomerization in vivo, attention thus needs to focus on (Z)-3-aminoacrylonitrile 10 as the most likely deamination product of cytosine aside from uracil.
本文讨论了胞嘧啶1的亚硝化脱氨反应，认为其通过1重氮化生成胞嘧啶重氮离子2及其静电复合物3，再脱重氮生成4⇌5，然后酰胺键断裂生成6。6可发生的反应通道包括水解去糖基化生成3-异氰酸基丙烯腈7、水加成到氨基甲酸9上并有可能重新闭环生成尿嘧啶13、水加成到氨基甲酸9上以及脱羧生成3-氨基丙烯腈10。鉴于氨基甲酸9的不稳定性，研究了氨基甲酸酯模型化合物(Z)-2-氰基乙烯基氨基甲酸乙酯14和(Z)-2-氰基-1-叔丁基乙烯基氨基甲酸酯20。14的酸催化水解生成2-氨基甲酰基苯基氨基甲酸酯15，其环化生成苯并稠合的尿嘧啶喹唑啉-2,4-二酮16。与芳香体系14不同，20的酸催化环化在与低聚反应竞争时不占优势，只有在碱催化下才能得到5-叔丁基尿嘧啶22。研究表明，10的母体23也容易发生聚合。实验结果解释了为什么在体外研究中9、10和12没有被检测到：它们会发生低聚反应。与体外实验不同，由于单体浓度较低，9、10或12在体内的低聚反应显然不相关。排除了体内的环化和低聚反应后，因此需要关注(Z)-3-氨基丙烯腈10，它是胞嘧啶除尿嘧啶外最可能的脱氨产物。
