Influence ofL-Cysteine on the Oxidation Chemistry of (-)-Epinephrine: Formation of Cysteinyl Conjugates and Novel Dihydrobenzothiazines

Oxidation of epinephrine (EPI) in aqueous solution at pH 7.4 generates anortho-quinone(1)that normally deprotonates and undergoes a rapid intramolecular cyclization and secondary reactions, ultimately leading to an indolic melanin polymer. In this investigation, it is demonstrated thatL-cysteine (CySH) can intervene in this reaction by scavengingo-quinone1to give 5-S-cysteinylepinephrine (5-S-CyS-EPI) and 2-S-cysteinylepinephrine (2-S-CyS-EPI). Subsequent oxidation (2e, 2H+) of the latter cysteinyl conjugates giveso-quinones that can either react further with free CySH to give the 2,5-bi-S- and 2,5,6-tri-S-cysteinyl conjugates of EPI or cyclize to give 7-[(2-methylamino)ethyl]-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-E1) and 8-[(2-methylamino)ethyl]-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-E2), respectively, Oxidations of 2,5-bi-S-CyS-EPI and 2,5,6-tris-S-CyS-EPI and of DHBT-E1 and DHBT-E2 in the presence of CySH provide routes to a number of other dihydrobenzothiazines (DHBTs). Four new cysteinyl conjugates of EPI and seven DHBTs have been isolated and their structures elucidated by spectroscopic methods. Based upon a number of lines of converging evidence, it is suggested that these compounds might include unusual metabolites of EPI formed in adrenergic neurons under certain pathological brain conditions.