New pyridobenzothiazine dimers from zinc catalyzed oxidation of 5-S-cysteinyldopa

Studies carried out in the last decade have elucidated in vitro pheomelanogenesis by 5-S-cysteinyldopa (CD) oxidation up to the 1,4-benzothiazine stage. Evolution of these species has however remained poorly defined. We report now a systematic re-examination of the oxidation of CD in presence of zinc ions. This metal, which occurs in human hair and epidermal tissues at significant levels, has an established stabilizing effect on pheomelanin intermediates. Under these conditions the oxidation of CD proceeds through 1,4-benzothiazine-3-carboxylic acid which is readily converted into a collection of products. Among these are the 2,2’-bi(2H-1,4-benzothiazine) dimers, trichocrome C, and two hitherto unknown species, sharing a pseudomolecolar ion peak [M+H]+ at m/z 515 for dimeric structures. These species were easily converted under the reaction conditions to the oxidized forms ([M+H]+ at m/z 513), A and B, which could be isolated and subjected to spectral analysis. Compounds A and B proved to be regioisomers featuring a novel pyridobenzothiazine system linked to a benzothiazole unit. A possible formation route of these novel compounds via benzothiazine ring contraction and side-chain cyclization to give pyridine unit is proposed.