Aporphine alkaloids boldine

Aporphine Alkaloids.—A study on the biosynthesis of boldine previously published in preliminary form and reviewed73 is now available in full74 without the addition of essentially new information. 

Nicotine and related pyridine alkaloids (A) Ammodendrine (A) anabasine (A) arborine (AA) boldine and other aporphine alkaloids (AA) berberine and related protoberberine alkaloids C-toxiferine (AA) coniine and related piperidine alkaloids (A) cytisine, lupanine, and other quinolizidine alkaloids (A) tubocurarine (AA) codeine (A) erysodine and related Erythrina alkaloids (AA) histrionicotoxin (AA) lobeline (A) methyllycaconitine (AA) pseudopelletierine (A)... 

Apomorphine was the most potent of the protein kinase inhibitors (IC50 for PKA-catalytic subunit 1 pM). However, the methylated aporphine alkaloid analogues of apomorphine such as bulbocapnine, isocorydine, glaucine and (+)-boldine were either inactive or poor inhibitors of this en2 yme. 

In practice a particular aporphine alkaloid may be derived a priori from a number of diphenolic benzylisoquinoline precursors either by direct coupling or through the genesis of a dienone intermediate as seen above. Thus in the study of the superficially simple alkaloid boldine (79), a number of benzylisoquinoline precursors had to be tested. Experiments were carried out with labelled samples of ( )-norprotosinomenine (83), ( )-nororientaline (84), ( )-4 -o-methyl-... 

The methylation pattern of boldine (79) might have been taken to indicate a biosynthetic pathway similar to that of the aporphine alkaloids of Dicentra but the above results clearly refute this idea. The change in the methylation pattern from reticuline (82) to boldine (79) is not apparently due to methyl migration for ( )-[6-0 CH3,l- H]reticuline [as (82)] was incorporated with loss of 64% of the labelsimilar results have been obtained in the related case of crotonosine biosynthesis. ... 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

Genotoxicity of the boldine aporphine alkaloid in prokaryotic organisms.Mwtot. Res. Genetic Toxicol, 260(2), 145-152. 

All that is required for the transformation of the benzylisoquinoline skeleton [as 6.123)] into that of the aporphines, e.g. bulbocapnine (5.729), is a single new bond. Clearly phenol oxidative coupling (N.B. see Section 1.3.1) is involved here, but there are several possible routes to a particular alkaloid. Interestingly examples of most of these possibilities have been found for the biosynthesis of one or more of the aporphine alkaloids, and in one case, that of boldine (5.757), biosynthesis takes a different course in two different plants. Methylation pattern in the alkaloid produced does not provide a reliable guide to the course of biosynthesis, as witness that of 6.131) in Scheme 6.25 [88]. The methylation pattern suggests a different pathway (see Scheme 6.27), which is followed in another plant. 

Nicotine boldine and other aporphine alkaloids C-toxiferine coniine and other piperidine alkaloids cytisine and other quinohzidine alkaloids epibatidine tubocurarine Berbamine, berberine, and other isoquinoline alkaloids cinchonidine and other quinoline alkaloids corynanthine, yohimbine, and other indole alkaloids emetine ephedrine ergometiine and related ergot alkaloids Ergocornine and related ergot alkaloids bulbocapnine and related aporphine alkaloids anisocycline, stylopine, and related protoberberine alkaloids salsolinol and related isoquinohnes BicuculUne, cryptopine, hydrastine, and related isoquinoline alkaloids securinine harmaline and related beta-carboline alkaloids Corymine, strychnine, and related indole alkaloids Histrionicotoxin and related piperidines ibogaine and related indole alkaloids nuciferine and related aporphine alkaloids... 

Akuammine and related indole alkaloids annonaine, boldine, and related aporphine alkaloids berberine and related protoberberine alkalodis ergotamine, LSD, and related ergot alkaloids psUocybine, bufotenine, N,N-dimethyltryptamine, and related indoles harmahne and related beta-carbohne alkaloids kokusagine and related furoquinoUne alkaloids mescahne ibogaine and other monoterpene indole alkaloids... 

Tbe aporphines constitute one of the largest groups of isoquinoline alkaloids and have a wide range of physiological activity. For example, bulbocapinine (93) (see Scheme 15) affects the central nervous system and causes catatonia, boldine... 

Transformations of aporphines by microorganisms involving O- and N-demethylation (89, 92) and CH—CH dehydrogenation (92) have been reported. In a preliminary screening study, Wolters reported the metabolism of boldine and a related alkaloid of undisclosed structure to unidentified products by Piricularia oryzae (42). More detailed studies with a series of microorganisms have been carried out by Rosazza and co-workers (89, 92). 

As a follow up to the above findings, it was observed that photolysis of the bromodiphenol (27) in ethanolic NaOH gave rise to the neoproaporphine (28) in 34% yield, together with AT-ethoxycarbonylnorboldine (29) in 5% yield. Further photolysis of the neoproaporphine (28) in NaOAc in ethanol produced a 44% yield of the aporphine (29) which could be cleanly reduced with LiAlH4 in THF to boldine (30), thus providing the first total synthesis of this alkaloid. ... 

The bark of Phoebe grandis (Lauraceae) gave the known aporphines, boldine, norboldine, laurotetanine and lindecarpine while the leaves yielded two new alkaloids, phoebegrandines A (26) and B (27) [37], which belong to the rare proaporphine-tryptamine group of compounds exemplified by roehybridine (28) (syn series) and roemeridine (29) (anti series) from Roemeria hybrida [38,39], The structure of 29 was previously established by X-ray analysis [40]. 

In the present chapter, we showed that boldine is the main alkaloidal constituent of the Chilean medicinal plant, boldo. Boldine shows potent antioxidant activity and free radical scavenging effects both imder in vitro and in vivo conditions. We also showed that the antioxidant activity of boldine is due to the presence of phenol groups in the aporphine ring of its chemical structure. In view of the multiple applications of boldo in the traditional medicine, it can be concluded that boldine causes no adverse effects and therefore it could be used as antioxidant for mitigation of oxidative stress. Nevertheless, there is no clinical study... 

Milian, L., Estelles, R., Abarea, B., Ballesteros, R., Sanz, M. J., Blazquez, M. A. (2004). Reaetive oxygen speeies (ROS) generation inhibited by aporphine and phenanthrene alkaloids semi-synthesized from natural boldine. Chem. Pharm. Bull, 52(6), 696-699. 

In a different approach, photolysis of the brominated diphenolic tetra-hydrobenzylisoquinoline 4, in which the nitrogen function is protected as a urethan, produced the neoproaporphine (or proerythrinadienone) 5 in 347 yield, together with //-ethoxycarbonylnorboldine (6) in 5% yield. Further photolysis of 5 in ethanol containing sodium acetate gave a 447, yield of the aporphine 6. This material could be easily reduced with lithium aluminum hydride to boldine (7), thus providing the first total synthesis of this alkaloid. 

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