Mechanism and Products of Autoxidation of 5,7-Dihydroxytryptamine

Article abstract of DOI:10.1021/ja00311a065

The neurodegenerative effect of 5,7-dihydroxytryptamine (5,7-DHT) has been postulated to involve alkylation of neuronal proteins by its autooxidation product, which is believed to be corresponding p-quinone imine (5,7-DHTQ).To more precisely elucidate the mechanism of autoxidation of 5,7-DHT and its molecular mechanism of action in vivo, a series of methyl-substituted 5,7-DHT's, namely, 4-Me-, 6-Me-, and 4,6-Me2-5,7-DHT's (21a-c, respectively), were designed and synthesized as probes.The indole nucleus of these probes was constructed by the reductive cyclization of the corresponding 2,β-dinitrostyrene and the aminoethyl side chain was introduced via gramine methiodides.Cyclic voltammetric analysis of 5,7-DHT and 21a-c in 0.1 M H2SO4 and pH 4.0 and 7.4 buffers indicated that the primary product of electrochemical oxidation from each compound is the corresponding p-quinone imine which is very short lived (< 1 s).Like 5,7-DHT, 21a-c exhibited phenol-keto tautomerism but 21a and 21c did so to a much smaller extent as determined by UV and NMR spectroscopic methods.The predominant nonphenolic tautomeric form of 5,7-DHT, out of eight possible, was shown to be 27 (R1=R2=H).Polarographic measurements showed that, like 5,7-DHT, 21a-c react with O2 in a bimolecular fashion.Consideration of all the data indicates that the initial product of autoxidation in all cases is apparently a 4-hydroperoxy derivative.Only in the case of 5,7-DHT and 21b, the initially formed hydroperoxides break down to give colored products.These products were not stable enough to be isolated, but their UV-visible spectra correlate very well with similar known structures.The structure of this product in the case of 5,7-DHT is postulated to be the (4,7)p-quinone of 4,5,7-trihydroxytryptamine (4,5,7-THTQ, 35, R=H).The results of this study further indicate that in the autoxidation of 5,7-DHT, the p-quinone imine (5,7-DHTQ) is almost certainly not the primary product nor is it a transient intermediate in the formation of 4,5,7-THTQ. 4,5,7-THTQ also is unstable and appears to undergo further transformations at pH 7.4.