title: Zinc-catalyzed oxidation of 5-S-cysteinyldopa to 2,2'-bi(2H-1,4-benzothiazine): tracking the biosynthetic pathway of trichochromes, the characteristic pigments of red hair.
abstract: Trichochromes, the peculiar pigments of red human hair, featuring the Delta(2,2)(')-bi(2H-1,4-benzothiazine) skeleton, are known to arise from cysteinyldopas, mainly the 5-S-isomer (5). However, the mode of formation and the direct precursors have remained largely undefined. To fill this gap, we investigated the oxidation of 5 in air or with chemical and enzymatic agents under biomimetic conditions. In the presence of zinc ions, which occur in epidermal tissues at significant concentrations, the reaction course is diverted toward the formation of a labile 3-carboxy-2H-1,4-benzothiazine intermediate (11), which was identified by direct NMR analysis. Structural formulation was supported by characterization of the analogous compound 13 isolated from oxidation of the model 5-methyl-3-S-cysteinylcatechol (12) after methylation. In the further stages of the oxidation, diastereomeric 2,2'-bi(2H-1,4-benzothiazine) 15 and 14 were obtained from 5 and 12, respectively, the reaction proceeding at a higher rate and to a greater extent in the presence of acids. The dimers were shown to readily convert to each other in the presence of acids. In the case of the methylated dimers 14, a 2,2'-bi(4H-1,4-benzothiazine) intermediate (16) was isolated and characterized. In acidic media, trichochrome C (1a), the most abundant in red human hair, was smoothly formed from aerial oxidation of 15, and under similar conditions, trichochrome-related products (17 and 18) were obtained from 14 prior to or after methylation. The presence of 1a and precursors 5 and 15 was investigated by HPLC analysis of red hair samples following mild proteolytic digestion. On the basis of these data, a likely biosynthetic route to trichochrome pigments of red human hair is depicted.
authors.affiliation: Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Via Cinthia 4, I-80126 Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Napolitano
authors.forename: P
authors.initials: P
authors.lastname: Di Donato
authors.forename: G
authors.initials: G
authors.lastname: Prota
mesh_terms: D002273:Carcinogens / Q000737:chemistry; D002384:Catalysis; D003548:Cysteinyldopa / Q000378:metabolism*; D006200:Hair Color; D006801:Humans; D010084:Oxidation-Reduction; D010860:Pigments, Biological / Q000737:chemistry* / Q000378:metabolism*; D013843:Thiazines / Q000737:chemistry* / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry
chemical_list: D002273:Carcinogens; D010860:Pigments, Biological; D013843:Thiazines; D003548:Cysteinyldopa; C022857:trichochrome C; D015032:Zinc