Alkaloid Formation in Mammals as a Therapeutic Concept

A two-electron oxidation of N-acetyltyrosine ethyl ester with mushroom tyrosinase, or with periodate, afforded the N-acetyIdopa ester 142, together with the (Z)-enamide 145 and the 6-acetoxydopa amide 146 (Fig. 40) (284). It is assumed that 145 originates from dopaquinone 143 via 144 by tautomerization. Michael addition of acetate to quinone 143 is believed to be the origin of 146. The formation of quinone methide 144 from dopa ester 142 by tyrosinase is reminiscent of the formation of iminochromes and quinone methides catalyzed by this enzyme in their formation from a-methyl dopa ester (285), and such reactions may well occur in mammalian systems. 

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

Electrochemical oxidation of racemic salsolinol (SAL) was investigated in aqueous solution at physiological pH (29/) (Fig. 42). The initial step was a reversible two-electron oxidation of SAL to the short-lived ortho-quinone E, isolated as the more stable quinone methide C. Further reaction of E, probably via quinone methide F and addition of water, yielded c/5-alcohol A and fra/i5-alcohol B, which are shown in an arbitrarily chosen configuration. Another product which was isolated is the fully aromatic isoquinoline D. Alcohols A and B are chemically related to the condensation product obtained from epinephrine and acetaldehyde (165). 

The interest in the National Institutes of Health mammalian alkaloid program by Dr. Bernhard Witkop. NIH Institute Scholar, and his help in finalizing this review are gratefully acknowledged. 

Holmstedt, in Beta-Carbolines and Tetrahydroisoquinolines. p. 3. Alan R. Liss, New York, 1982. 

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