Berberine and Related Alkaloids

Berberine as a member of the class of compounds classified by Hantzsch 73) as pseudo bases has commanded its share of discussion on this still controversial topic. The generally accepted view of Gadamer (74) that berberine exists in solution as an equilibrium mixture of three tautomeric forms (la-c) has been reexamined (75). 

The evidence for the existence and structures of the ammonium form (la) and the pseudo-base form (Ib) is well established and was discussed in more detail in the previous review of these alkaloids (Volume IV, Chapter 5). More recent elForts have been concerned with seeking evidence for the presence of the aldehyde form (Ic) and the possibility of its participation in certain reactions of berberine. 

The chemical approach to the study of this problem is beset with the usual difficulties encountered in a system containing several rapidly equilibrating forms in w hich each is capable of undergoing reaction with a given reagent. Certainly alkylation, which occurs at C-8 with nucleo- 

asiatica Roxburgh (35) Berberine Palmatine Jatrorrhizine Berbamine 

hauniensis Zab. 36) Berberine Berberubine Jatrorrhizine Palmatine Berbamine Columbamine Oxyaoanthine 

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These hypotheses, although not always correct, have been of inestimable value in guiding tracer experiments on living plants. Experiments on the biosynthesis of berberine and related alkaloids have had, in addition to these guidelines, the benefit of the knowledge gained from previous tracer studies on the biosynthesis of the isoquinoline alkaloids of the papaverine and the morphine series, where it was known that two molecules of the aromatic amino acid, tyrosine, are built into these alkaloids via a pathway involving the intermediacy of norlaudanosoline (XCIV). 

Spenser and co-workers 123) have investigated the biosynthesis of berberine and related alkaloids elaborated by Hydrastis canadensis L. In separate feeding experiments, D-glucose-i C (uniformly labeled), DL-phenylalanine-2-i4C, DL-tyrosine-2-i4C DL-tyrosine-S-i C, and 3,4-dihydroxy-2-phenylethylamine-l-i4C (dopamine) were administered to the growing plants. Of the compounds tested tyrosine was the most efficient precursor of the major alkaloids, berberine and hydrastine, and dopamine was almost as good. Glucose was a much less efficient precursor, and the incorporation of phenylalanine into these alkaloids was almost negligible. 

Biosynthesis of berberine and related alkaloids is based on the transformation of phenylalanine. The tetracyclic skeleton (derived from benzytetrahydroisoquinoline) arises by incorporation of the JV-methyl group (so-called berberine bridge) in alkaloid reticulin, which is the immediate precursor of berberine. 

Active Constituents Protopine, berberine (morphine-related alkaloids), and several isoquinilines. 

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)... 

Application of different molecular orbital methods to the calculation of electron densities of quinolizinium ion and its benzo derivatives led to the results summarized in Table 2. It can be appreciated that in these compounds, nitrogen atoms receive electron density from carbon atoms of the opposite parity, as suggested by perturbation theory <92AHC(55)26i>. Similar Htlckel molecular orbital calculations on berberine (15) and related alkaloids gave an uncommonly high positive... 

C. Tani, K. Tagahara, Studies on berberine derivatives and related alkaloids VII, Chem.Pharm.Bull. 22 (1974), 2457-2459. 

In some alkaloid reference volumes, alkaloids such as berberine and related molecules have been classified as benzo[r]phenanthrene alkaloids. We have chosen to classify these alkaloids, for the purposes of this review, as isoquinoline-derived alkaloids, which are discussed in Section 7.9. Isoquinoline is the largest constituent of these alkaloids that falls into a trivial classification, which was the basis of our decision. 

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... 

Galanthamine physostigmine and related indole alkaloids berberine and related protoberberine alkaloids vasicinol and related quinazolines ... 

It should, however, be noted that though Spath and Kruta were unable to condense tetrahydropapaverines with formaldehyde to the berberine type of alkaloid, they found that tetrahydropapaverolines condensed with formaldehyde in both ways, and examples will be found under corydaline (p. 289) and the constitution of palmatine and the related bases (p. 343). 

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. 

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

Fluorescence data for the interaction with acetylcholinesterase (EC 3.1.1.7, ACHE) from the electric eel Electrophorus electricus with some quaternary protoberberine and benzophenanthridine alkaloids was obtained. Berberine and other related compounds were bound to the gamma y-anionic site of ACHE via a comparison with known inhibitors of acetylcholinesterase, including tetramethylammonium and tacrine. Furthermore, during the interaction, two molecules of the ligand were bound to one molecule of the enzyme [226]. 

Some protoberberine and structurally related alkaloids were tested for inhibitory activity on porcine pancreatic elastase (PPE) and human sputum elastase (HSE). Berberine chloride significantly inhibited the elastolytic activity of both enzymes, but tetrahydroberberine had no effect. It appears that the quaternary nitrogen atom of these alkaloids plays an important role in the inhibition of elastolytic activity. The amidolytic activity of the elastases was not affected by any of the test alkaloids [240]. 

The quaternary isoquinoline alkaloid berberine (28) is widely used in Asia as a drug. Among other maladies, diarrhea, dysentry, cholera, and eye infections are indications for which berberine or plant extracts containing this alkaloid are applied, because of the antimicrobial activity of berberine (472,506). Berberine interacts with DNA, but this does not seem to be related to its antimicrobial activity (506). Berberine contracts also uterine muscle and is used to stop uterine bleeding. Furthermore berberine has an anti-inflammatory effect (507). In Japan berberine and in particular extracts of dried rhizomes of Coptis japonica Makino var. dissecta (Yatabe) Nakai (Ranunculaceae) are widely used as a stomach tonic. 

Important work on alkaloids, particularly quinine, was done by Skraup (see p. 837) and his collaborator Wilhelm Konigs (Diilken, 22 April 1851-Munich, 15 December 1906), a pupil of Kekule and professor in the University of Munich. R. F. Pschorr, professor in the Technical High School, Char-lottenburg, worked on the synthesis of phenanthrene derivatives and their relation to morphine and other alkaloids. The important work on berberine and harmaline by W. H. Perkin jimr. and collaborators can only be mentioned. 

Subsequent to its CjMDRl-catalyzed uptake into the cytoplasm, the final accumulation of berberine in Coptis rhizome cells occurs in the vacuole by a different mode of transport. The tonoplast harbours a H /berberine antiporter that operates with a Km of about 45 pM for berberine (Fig. 5). Competition experiments with berberine analogs and non-related alkaloids revealed that this transporter is fairly specific, although not exclusive, for berberine (Otani et al, 2005). 

As one outcome of an investigation into methods for the synthesis of the berberine type of alkaloid by Perkin and his collaborators, in the course of which an extensive series of bases related to, or associated with berberine, including the interesting linear berberine paraberine), were prepared, Haworth, Perkin and Pink devised a general method for such syntheses, of which examples are given under protopine (p. 299) and cryptopine (p. 295), and which was applied by Haworth, Koepfli and Perkin to oxyberberine and palmatine (p. 342). For these two alkaloids it involved the preparation of 3 4-dimethoxyfeonjophthalic anhydride, which was condensed with )S-piperonylethylamine and the resulting phlhalamic acid (XXIII), as the methjd ester, boiled with phosphorus oxychloride, which converted it into oxyberberine (XXH). 

The isoquinoline (9-44) or benzyltetrahydroisoquinoline skeleton, respectively, can be found in the tetracyclic alkaloid berberine, also called umbellatin (9-45). Together with related alkaloids, berberine occurs in all parts of the European barberry shrub Berberis vulgaris, Berberidaceae) as the main component, especially in the cortex, but also in leaves and immature fruits. Barberry alkaloids are carriers of the characteristic yellow colour of barberry wood and bark, but do not practically influence the colour of edible berries. The mildly poisonous cortex of the roots, containing 12-15% of alkaloids, was used in the past as a drug for medical purposes (the bark of stem contains 5.5-8% and the bark of branches about 3.5% of the mixture of alkaloids). The main components of the root bark are quaternary bases berberine (9-45), jatrorrhizine, columbamine, pahnatine (9-46) and tertiary bases oxyacanfhine (9-47) andberbamine (9-48). 

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