Grivas S
Department of Chemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Princess Takamatsu Symp. 1995;23:1-8.
A review of five different routes to the synthesis of the grilled or fried food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and of closely related compounds developed in different laboratories is presented. Interest in the synthesis of these amines began in the late 1970s when the research group led by Professor T. Sugimura (National Cancer Center, Tokyo) detected extremely high mutagenicity in the charred parts of fish and meat that could not be explained only by the presence of polyaromatic hydrocarbons. A number of new mutagenic heterocyclic amines have been detected, isolated and identified since then (de Meester, 1989; Overvik and Gustafsson, 1990; Felton and Knize, 1991; Jägerstad et al., 1991). It is still not entirely clear how these compounds are formed during cooking. For the "IQ-group" of the amines (2-amino-3-methylimidazo-quinoline and -quinoxaline congeners), a formation pathway from Maillard reaction products and creatinine was conceived by Professor K. Olsson (this laboratory) and presented at the 183rd meeting of the American Chemical Society, Las Vegas in 1982 (Jägerstad et al., 1983). However, the amounts of the amines formed during cooking or in model reaction systems are very small. Therefore, efficient and unambiguous synthetic methods yielding the compounds in isomerically pure form are required for reference purposes in analytical work and structure-biological activity studies. For instance, compare the mutagenicity of 4,8- and 5,8-DiMeIQx, and PhIP and its 3-methyl isomer shown on the following page. The pure compounds are also required in large quantities for long-term animal feeding studies. The length of this article does not allow a presentation of the published synthetic methods for all the heterocyclic amines. Therefore, the syntheses of only one of the food mutagens, 8-MeIQx, and some related compounds are presented. This will hopefully demonstrate the sort of problems the organic chemist encounters and some of their possible solutions. For a relatively recent reference list covering the synthesis, isolation, detection, formation and biological activity of these food mutagens and carcinogens the reader is referred to Hatch et al. (1988).
本文综述了五条不同的合成途径，用于制备烧烤或油炸食品中的致癌物2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（8-甲基咪唑喹喔啉）以及不同实验室开发的密切相关化合物。对这些胺类化合物合成的兴趣始于20世纪70年代末，当时由东京国立癌症中心的T. 杉村教授领导的研究小组在鱼和肉的烧焦部分检测到极高的诱变性，而这仅用多环芳烃的存在无法解释。从那时起，已经检测、分离和鉴定了许多新的诱变杂环胺（德梅斯特，1989年；奥弗维克和古斯塔夫松，1990年；费尔顿和克尼兹，1991年；耶格斯塔德等人，1991年）。目前仍不完全清楚这些化合物在烹饪过程中是如何形成的。对于胺类的“IQ组”（2-氨基-3-甲基咪唑喹啉和喹喔啉同系物），K. 奥尔松教授（本实验室）提出了一种由美拉德反应产物和肌酸酐形成的途径，并在1982年于拉斯维加斯举行的美国化学学会第183次会议上发表（耶格斯塔德等人，1983年）。然而，烹饪过程中或模型反应体系中形成的胺类化合物数量非常少。因此，为了分析工作和结构-生物活性研究的参考目的，需要高效且明确的合成方法来以异构体纯形式制备这些化合物。例如，比较下一页所示的4,8-和5,8-二甲基咪唑喹喔啉、苯并[a]芘及其3-甲基异构体的诱变性。长期动物喂养研究也需要大量的纯化合物。本文篇幅有限，无法介绍所有杂环胺已发表的合成方法。因此，仅介绍了一种食品诱变剂8-甲基咪唑喹喔啉以及一些相关化合物的合成。希望这能展示有机化学家遇到的一些问题及其可能的解决方案。关于这些食品诱变剂和致癌物的合成、分离、检测、形成和生物活性的相对较新的参考文献列表，读者可参考哈奇等人（1988年）的文献。
