Synthetic routes to the food carcinogen 2 amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and related compounds.
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).
Grivas
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Department of Chemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
D000818:Animals; D002273:Carcinogens / Q000138:chemical synthesis*; D003296:Cooking; D003314:Corn Oil; D004041:Dietary Fats; D005399:Fishes; D005609:Free Radicals; D006358:Hot Temperature; D006801:Humans; D015416:Maillard Reaction; D008460:Meat; D015394:Molecular Structure; D009153:Mutagens / Q000138:chemical synthesis; D000069463:Olive Oil; D010938:Plant Oils; D011810:Quinoxalines / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D002273:Carcinogens; D004041:Dietary Fats; D005609:Free Radicals; D009153:Mutagens; D000069463:Olive Oil; D010938:Plant Oils; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D003314:Corn Oil