4-Chloro-6-methoxyindole is the precursor of a potent mutagen (4-chloro-6-methoxy-2-hydroxy-1-nitroso-indolin-3-one oxime) that forms during nitrosation of the fava bean (Vicia faba).
Fava beans (Vicia 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 u.v., i.r., m.s. and n.m.r. The precursor was dechlorinated with NaBH4 and PdCl2 as 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. Thus, it appears that 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.
D007887:Fabaceae / Q000032:analysis* / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000302:isolation & purification*; D009153:Mutagens / Q000302:isolation & purification* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D010946:Plants, Medicinal; D013274:Stomach Neoplasms / Q000209:etiology
D007211:Indoles; D009153:Mutagens; D009573:Nitrites; D009602:Nitrosamines; C043300:4-chloro-6-methoxyindole; C043301:4-chloro-6-methoxy-2-hydroxy-N(1)-nitrosoindolin-3-one oxime