OXIDATIVE POLYMERIZATION OF THE PHEOMELANIN PRECURSOR 5-HYDROXY-1,4-BENZOTHIAZINYLALANINE - A NEW HINT TO THE PIGMENT STRUCTURE

Biosynthetic studies have shown that pheomelanins, the distinctive pig ments of red human hair, arise from oxidative polymerization of cystei nyldopas via 1,4-benzothiazinylalanine intermediates. However, the mod e of formation of the pigment polymer remains controversial. To addres s this point, we have investigated the conversion of the major biosynt hetic precursor 5-S-cysteinyldopa (2a) to pheomelanin under biomimetic conditions. Peroxidase/H2O2 oxidation of 2a was shown to lead in the early stages to the 1,4-benzothiazinylalanine 8a, which rapidly declin es with concomitant formation of a distinct pattern of oligomeric prod ucts. Reduction of the reaction mixture at this stage allowed the isol ation of dimer 17 in 10% yield, along with trimers 18 and 19 in smalle r amounts. A restricted rotation about the ethereal C-O bond of 17 was apparent by the presence of two NMR-detectable conformational isomers , separated by an activation energy barrier of 17.83 +/- 0.03 kcal mol (-1). Under similar oxidation conditions, the model catechol 2b gave t he related dimers 15 and 16. The structure of oligomers 17-19, all cha racterized by C-C and C-O bonds between the benzothiazine units, would suggest that the peroxidase-promoted polymerization proceeds by pheno l-type coupling of an aryloxy radical generated by initial one-electro n oxidation of 8a. Overall, these results point to a structural model for the pheomelanin polymer which is basically different from that pro posed on the basis of degradative studies.