Protoberberine and Related Alkaloids

Protoberberine and Related Alkaloids.—The benzylisoquinoline skeleton [as (64)], which appears in diversely modified form in various alkaloids [see, e.g., (66)—(71)], is formed from two molecules of tyrosine label from this amino-acid often appears equally divided over the two halves of the alkaloid examined,1,219 but dopa (60), like dopamine (59), is incorporated only into the isoquinoline moiety cf. Vol. 6, pp. 17, 26 Vol. 7, p. 10 Vol. 9, p. 8). 

The incorporation of dopa (60) has been further studied by examining its utilization in the formation of berberine (66) and hydrastine (67) in Hydrastis canadensis, corydaline (68) and protopine (70) in Corydalis solida, and ochotensimine (71) and protopine (70) in C. ochotensis.20 [2-14C]Dopa [as (60)] was again found to label only the isoquinoline moiety of these alkaloids (label is shown by ). 

Both tyrosine and methionine are precursors for corydaline (68) and ochotensimine (71) cf. Vol. 6, p. 23). Formation of ochotensimine (71) from L-[m t/iy/-3H,14C]methionine with high retention of tritium has been confirmed.20 

The berberine relative (72) has been found to be a precursor of corydaline (68), acting to provide the hypothetical intermediate (73) for introduction of the C-methyl group. Curiously, the likely precursor, i.e. (69), for both (72) and (73) was not incorporated.20 

Horseradish peroxidase, it has been observed, will oxidatively decarboxylate amino-acids such as (63).21 

Protoberberine and Related Alkaloids.—Recent extensive work has allowed detailed description of the biosynthesis of protoberberine alkaloids, e.g. tetra-hydrocoptisine (67), and bases derived from them. ° Results of a study on the interrelationships of Corydalis incisa alkaloids provide supplementary information, particularly in regard to the intermediacy of compounds of type (69).  

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Scheme 1. Biosynthetic relationships between protoberberines and related alkaloids.

Biosynthetic Studies of Protoberberine and Related Alkaloids Using Plant Cell Cultures... 

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]. 

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. 

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)... 

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]. 

This volume of The Alkaloids Chemistry and Biology might be called The Brazilian Volume since each of the three chapters is compiled and written exclusively by Brazilian authors. This is definitely a reflection of the tremendous current Brazilian interest in the investigation and potentiation of their vast array of natural resources, and particularly of alkaloid-bearing plants. In this volume, the recent progress relating to three groups of alkaloids, the protoberberine alkaloids, the Stemona alkaloids, and the alkaloids of the plant family Hernandiaceae is reviewed. 

There are numerous protoberberine- and tetrahydroprotoberberine-type alkaloids including berberine (9), coptisine, scoulerine, isocorypalmine and coreximine. Berberine contracts uterine muscle and has been used to stop uterine bleeding and to help in childbirth. Its action is relatively weak and uncertain and because it has somewhat toxic properties it is no longer used for these purposes. Berberine also exerts some antiinflammatory activity (Otsuka et al. 1981) and it does depress the formation of connective tissue. When berberine is infused in a dose of 0.2 mg kg it has a positive inotropic effect on dog heart, reducing heart rate and decreasing total peripheral resistance of blood circulation (Maroko et al. 1982). (—)-Coreximine (10), also found in opium, is closely related to berberine and it also acts with a positive inotropic effect on dog heart and reduces heart rate when it is infused with 0.2 mg kg . Coptisine (11) has an inhibitory effect on the formation of connective tissue (Otsuka et al. 1981). 

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... 

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

Several applications of this methodology have appeared from Mariano s group, however, we will demonstrate the synthetic potential of this discovery by citing here the two most important examples. Synthesis of ( +) Xylopinine (205), a protoberberine alkaloid, has been performed [161] from the photocyclisation of 204 in methanol. Similarly, a erythrane ring system (207) has been constructed [162] from the photoreactions of 206. Some other interesting aspects of this chemistry have been related to a novel Pictet-Spengler [163] type cyclisation and the chemistry of allene cation radicals [164]. 

In a related reaction, treatment of protoberberines (142) with alkyl chloroformates afforded compound (143) (Equation (13)), arising from cleavage of the Cs—bond and useful as a building block in alkaloid synthesis <82H(19)1895, 83H(20)2417>. This regioselectivity is not always achieved, and the Ce—N bond can also cleave to give a mixture <787635,79H(12)497,81H(15)297>. 

The Papaveraceae and Fumariaceae DC. are closely related families. Their relationship as well as their independence are well demonstrated by the external stmcture of the flowers, the various anatomical characteristics of their different organs, and alkaloid content. As in the Papaveraceae, the protoberberines, ben-zophenanthridines, and protopines are chemotaxonomically significant for the Fumariaceae. Characteristic for the Fumariaceae is the presence of spirobenzylis-oquinolines, indenobenzazepines, secophthalideisoquinolines, phthalideiso-quinolines, and cularines. The Fumariaceae also contain quaternary highly polar alkaloids, insoluble in nonpolar solvents (16). 

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