4-Chloro-6-methoxyindole is the precursor of a potent mutagen (4-chloro-6-methoxy-2-hydroxy-1-nitroso-ndolin-3-one oxime) that forms during nitrosation of the fava bean (Vicia faba)

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Abstract
Fava beans (V. faba) upon treatment with nitrite under simulated gastric conditions, form a direct-acting bacterial mutagen, comparable in specific activity to the most potent known mutagens for several strains of Salmonella typhimurium. The precursor of the mutagen was isolated and identified as 4-chloro-6-methoxyindole by UV, IR, m.s. [mass spectronomy] and NMR. The precursor was dechlorinated with NaBH4 and PdCl2 was the catalyst and the product obtained from this reaction was identified as 6-methoxyindole. Since synthetic 4-chloro-6-methoxyindole was not available, structure activity studies were conducted on substituted indoles. Nitrosation of 4-chloroindole closely follows the results for nitrosation of 4-chloro-6-methoxyindole. The major product of nitrosation of 4-chloroindole is 4-chloro-2-hydroxy-N1-nitroso-indolin-3-one oxime. Apparently the major nitrosation product of 4-chloroindole and of 4-chloro-6-methoxyindole is a stable .alpha.-hydroxy N-nitroso compound. This is the first reported case of stable .alpha.-hydroxy N-nitroso compounds. In the presence of N-(1-naphthyl)ethylenediamine dihydrochloride (NEDD), the .alpha.-hydroxy N-nitroso compound rearranges to an aromatic diazonium ion which couples with the diamine to form an azo dye. Studies on nitrosation kinetics indicate that the nitrosation of indoles are relatively fast reactions. Both the structural and rate studies give strong support to the hypothesis that intragastric nitrosation of fava beans yield the putative gastric carcinogen in the high-risk area in Colombia.

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