Isoquinoline alkaloids protoberberine

Abstract Protoberberine alkaloids and related compounds represent an important class of molecules and have attracted recent attention for their various pharmacological activities. This chapter deals with the physicochemical properties of several isoquinoline alkaloids (berberine, palmatine and coralyne) and many of their derivatives under various environmental conditions. The interaction of these compounds with polymorphic DNA structures (B-form, Z-form, H -form, protonated form, triple helical form and quadruplex form) and polymorphic RNA structures (A-form, protonated form, triple helical form and quadruplex form) reported by several research groups, employing various analytical techniques such as spectrophotometry, spectrofluorimetry, circular dichro-ism, NMR spectroscopy, viscometry as well as molecular modelling and thermodynamic analysis to elucidate their mode and mechanism of action for structure-activity relationships, are also presented. 

The protoberberine alkaloids (5-75) play important roles as precursors in the biosynthesis of a variety of related isoquinoline alkaloids such as protopine, phthalideisoquinoline, spirobenzylisoquinoline, rhoeadine, inde-nobenzazepine, secoberbine, and benzo[c]phenanthridine alkaloids. Chemical transformations of protoberberines to these alkaloids are particularly interesting and exciting from the biogenetic viewpoint and further from ready availability of starting protoberberines in nature or synthesis. 

The 6,7-secoberbine alkaloids contain the four following natural products corydalic acid methyl ester (55), corydamine (56), N-formylcorydamine (57), and hypecumine (58). These bases, called 3-arylisoquinolines, were described by Shamma and Moniot (2) as a separate class of isoquinoline alkaloids. Santavy (7) classified them among benzophenanthridines. It seems, however, that they may be considered as biosynthetic intermediates between the protoberberines on the one hand and the benzophenanthridines on the other. 

The protoberberine alkaloids occupy a prominent seat among the isoquinoline alkaloids. They are widely distributed in higher plants, occurring in at least nine... 

Another common structural component of the isoquinoline alkaloids, particularly in the protoberberines, is the 7,8-disubstituted 1,2,3,4-tetrahy-droisoquinoline unit. The spectrum of 7,8-dimethoxy-l,2,3,4-tetrahydroiso-quinoline (4) showed two interesting chemical shift changes other than the expected shifts in the aromatic carbon atoms (14). First, it was found that C-l was shielded relative to the corresponding carbon atom of 2 by —4.6 ppm. This was attributed to the y steric effect of the C-8 methoxyl group on... 

A number of plants produce laticifers filled with latex. For example, isoquinoline alkaloids in the family Papaveraceae are abundant in the latex (59), where they are sequestered in many small latex vesicles. In latex vesicles of Chelidonium majus the concentration of protoberberine and... 

The Rutaceae are known as a large plant frunUy with approximately ISO genera and 1,000 to 2,000 swedes, chemically characterized by numerous alkaloids of extensive structural diversity. Some isoquinoline alkaloids are known in this family of which especially aporphines, protopines, protoberberines, and benzo[c]phenanthridines are common in the Papave-... 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

Preformed cyclic /V,A-dialkyliminium salts i.e. where a ring Joins the a-caibon and positively charged nitrogen) have been used in enolate condensation reactions. The number of examples, however, is rather limited, probably because of complications arising through abstraction of enolizable protons. A -Dehy-droindolizidinium salt (69) represents one of the few examples of an enolizable, cyclic A, -dialkylimi-nium salt known to react with an enolate (equation 8). The use of a soft zinc enolate in this reaction may be crucial. The relative stereochemistry of the resulting 3-amino ester (70) is undefined. /V-Alkyl-3,4-dihydroisoquinolinium salts e.g. 71), a class of nonenolizable, cyclic iminium salts, have had extensive applications in the total synthesis of protoberberine and phthalide isoquinoline alkaloids. A review by Pai and coworkers has covered much of this work. In a more recent application by Yamazaki and co-... 

CycUzations. Bromoarenes form radicals that can be exploited in synthesis, including cyclization routes to aporphines-indolo[2,l-a]isoquinolines, and protoberberine-pavine alkaloids. ... 

A number of reviews on various aspects of QBA have been published. The principal information can be found in the two books on isoquinoline alkaloids by Shamma [1,2] and the reviews by Santavy [3,4] and Simanek [5] in The Alkaloids series. A highly valuable review of the physical and spectral data and the occurence of the 88 benzophenanthridine alkaloids has been compiled by the Shamma group [6], Preininger has summarized the distribution of QBA in plant species of the Papaveraceae and Fumariace-ae families [7]. A review by Dostal and Potacek specifically devoted to the in vitro nucleophilic conversions of QBA appeared in 1990 [8], Surveys on the biological activities [9-11] and biosynthetic formation [12,13] of these alkaloids have been published. Well-designed reviews of the syntheses of the QBA are also available [14-16]. Hanaoka and Mukai presented a treatise on the biomimetic syntheses of the benzophenanthridines from the protoberberines in volume 14 of the Studies in Natural Products Chemistry series [17]. Quite recently, a book by Bentley treating isoquinoline alkaloids also involved benzophenathridines [18]. 

In Ottawa he began a systematic investigation of Fumariaceous plants for their alkaloid content. By developing new methods of separation of the alkaloids he found many new bases of the aporphine, benzophenanthridine, phthalideisoquinoline, protopine, and protoberberine ring systems. Three new classes of isoquinoline alkaloids also owe their discovery to this work. In his examination of Dicentra cucullaria he found the alkaloid cularine, determined its structure, and thereby demonstrated that it belonged to a new ring system. In the same period he isolated many of the alkaloids that are now known as the spirobenzylisoquinolines. Some 25 years later he was... 

The usefulness of benzocyclobutenyl derivatives for the synthesis of isoquinoline alkaloids (see Vols. 2—4 of these Reports) has been extended to the preparation of the protoberberine bases (Schemes 9 and 10). In one case (Scheme 9), compound (155) was thermolysed to afford the protoberberinium salt (157), the reaction plausibly proceeding via the ortho-quinonoid intermediate (156), which then undergoes electrocyclization and dehydrogenation to give the product. Reduction of (157) then provided the protoberberine (158 R = H, R = R = Me). This route was used for the synthesis of (+ )-discretine (158 R = H,... 

Many of the alkaloids of the isoquinoline group— particularly those belonging to the protoberberine, cryptopine, and phthalideisoquinoline subgroups—are uterine stimulants. Their action in vivo, however, is very fleeting. In connection with the isoquinoline alkaloids, it should be mentioned that relaxation of smooth muscle is a property long associated with the benzylisoquinoline compounds. Occasionally we find this property loosely applied to isoquinoline compounds in general. The fact that a large number of isoquinoline compounds are active uterine stimulants clearly indicates that such statements are not entirely in line with the facts. 

The biosynthesis of protoberberine alkaloids, including berberine, has been extensively studied, and all the enzymes of the biosynthetic pathway have been characterized (11,121,391,508). Interestingly the pathway leading to berberine in Berberis was found to be different from that in Coptis and Thalictrum (509). In the former species berberine is formed from columbamine, in the latter plant species from tetrahydroberberine (121). The production of isoquinoline alkaloids, including the protoberberine alkaloids, by plant cell cultures have been reviewed by Riiffer (390) and Ikuta (510). Table XXVI summarizes patents concerning the production of berberine by means of plant cell cultures. In Table XXVII a summary is given of the occurrence of berberine in some plant cell cultures. 

Benzyl(tetrahydro)isoquinoline alkaloids. B. a. occur especially in various Annonaceae, Lauraceae, Rhamnaceae, Ranunculaceae, Papaveraceae, and Fa-baceae. They are soluble in ethanol, chloroform, ether and poorly soluble in water. Laudanidine is toxic, it acts as a convulsive and respiratory stimulant, laudan-osine is a tetanic toxin, orientaline is the biosynthetic precursor of isothebaine. Pwtosinomenine occurs especially in Erythrina lithosperma (Fabaceae). Papaverine [ 1 -(3,4-dimethoxybenzyl)-6,7-dimethoxyiso-quinoline] acts as a parasympathicolyticum relaxing smooth musculature, it promotes cerebral perfusion (vasodilatation). It is an antiasthmatic and oral anti-spasmodic agent used in the treatment of gastrointestinal spasms LD50 (mouse i. v.) 25 mg/kg. Reticuline is an important precursor of protoberberines, morphi-nans, aporphines, spirobenzylisoquinolines, and rhoeadine alkaloids. 

BiosynthesisP. a. are formed from benzyl(tetrahy-dro)isoquinoline alkaloids such as reticuline via the protoberberine alkaloid (5)-scoulerine, probably by way of ophiocarpine. 

Protoberberine alkaloids. Most P. a. occur as tetra-hydroprotoberberines or as protoberberinium salts. The P. a. are among the most widely distributed group of the isoquinoline alkaloids, they occur in at least 9 plant families, especially in Annonaceae, Berberida-ceae, Lauraceae, Menispermaceae, Papaveraceae, and Rutaceae, as well as in Fumariaceae (see table). 

Fig. 2. Alkaloid biosynthetic pathways are associated with a diverse variety of cell types. The tissue-specific localization (shaded) of enzymes and/or gene transcripts are depicted for the biosynthesis of tropane alkaloids in Atropa belladonna and Hyoscyamus niger roots (A), monoterpenoid indole alkaloids in Catharanthus roseus leaves (B), pyrrolizidine alkaloids in Senecio vernalis roots (C), pyrrolizidine alkaloids in Eupatorium cannabinum roots (D), benzyl-isoquinoline alkaloids in Papaver somniferum vascular bundles (E), and protoberberine alkaloids in Thalictrwn flamtm roots (F).

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