Berberines and Tetrahydroberberines

The absolute configurations of thalidastine and berbastine, the two known 5-hydroxy-berberines, have been determined by inference from the observation that the analogue (23) is dextrorotatory as are these alkaloids. The hydroxy-base (23) was prepared from (+)-tetranydrojatrorrhizine by oxidation with lead tetraacetate, followed by hydrolysis to give a 2 1 mixture of the alcohols (24 R = H, R = OH) and (24 R = OH, R = H), the configurations of 

Xylopinine has been syntnesised by photochemical cyclisation of (34 R = COgMe) and (34 R = to the related 

The following species have been shown to contain the alkaloids stated  

Cryptocarya longifolia14 Fumaria judaica111 Fumaria schleicheri112 Meconopsis cambrica113 Stephania glabra114 Thalictrum alpinum13 

The chemistry of the alkaloids of this group has been reviewed.117,118 Dehydrodiscretine (29 R1 = R2 = Me) and thalifaurine (29 R R2 = CH2) are novel alkaloids, and their structures have been determined by spectroscopic methods, reduction, and synthesis.115 An alkaloid named fumajudaine has been shown to be identical with stylopine.111 

Taborska, F. Veznik, and J. Slavic, Collect. Czech. Chem. Commun., 1980, 45, 1301. 

Kiryakov, Z. Mardirosyan, and P. Panov, Dokl. Bolg. Akad. Nauk, 1980, 33, 1377. 

Alkaloids of this group have been isolated as follows  

Monanthotaxis cauliflora73 Pachypodanthium staudii74 Papaver rupifragum75 Thalictrum minus76 Thalictrum rugosum12 

Of these bases, (-)-ophiocarpine AT-oxide is a new natural product,71 (+)-10-desmethylxylopine is a new alkaloid that is isomeric with govanine,72 and staudine is a new base that has been shown to have the bridged tetrahydroberberine structure (38) by spectroscopic studies and an X-ray crystallographic examination.74 

---

Berberine inhibits oxidative decarboxylation of yeast pyruvic acid (310) the same dose has, however, no effect upon aerobic glycolysis, Warburg s respiratory enzymes, indophenol oxidase, etc. Berberine and tetrahydroberberine have an inhibitory effect on oxidation of (+ )-alanine in rat kidney homogenates (498). Berberine and palmatine show a specific inhibitory effect upon cholinesterase in rabbit spleen and on pseudocholinesterase in horse serum (499). Berberine inhibits cellular respiration in ascitic tumors and even in tissue cultures (500-502). The specific toxic effect of berberine on the respiration of cells of ascitic tumors in mice was described (310). The glycolysis was not found to be affected, but the uptake of oxygen was smaller. Fluorescence was used in order to demonstrate berberine in cellular granules. Hirsch (503) assumed that respiration is inhibited by the effect of berberine on the yellow respiratory enzymes. Since the tumorous tissue contains a smaller number of yellow respiratory enzymes than normal tissue it is more readily affected by berberine. Subcutaneous injections of berberine, palmatine, or tetrahydropalmatine significantly reduce the content of ascorbic acid in the suprarenals, which is not affected by hypophysectomy (504). 

The relative proportions of VI and VII obtained from the intermediate salt VIII (R = H) apparently vary with the nature of the reducing agent zinc-acid systems aiford corydaline predominantly 79) while boro-hydride reduction 80) is claimed to give corydaline exclusively. Products of types VI and VII may not originate exclusively from reduction of the imonium salt since a recent investigation (5i) of the reaction of methyl iodide with dihydroberine has indicated the imonium salt corresponding to VIII (R = H) readily disproportionates to berberine and tetrahydroberberine (IX). 

Since both the dopamine and noradrenaline experiments gave berberastine of a much higher specific activity than that found in berberine and tetrahydroberberine, the latter alkaloids cannot be precursors of berberastine. Further, since noradrenaline is efficiently incorporated into berberastine, whereas berberine and tetrahydroberberine from this experiment have negligible activity, the C-5 hydroxyl group must be introduced at an early stage in the biosynthesis, certainly prior to the formation of the benzylisoquinoline intermediate. 

Preliminary characterization of some of the other intermediates involved in the biosynthesis of berberine in H. canadensis has been reported. Both the isomeric ( + )-norreticulines XCIXa and XCIXb are efficiently incorporated into berberine indicating that each is methylated to reticuline. Evidence for postreticuline intermediates is less equivocal. (+ )-Tetrahydroberberubine-12-3H (C) was only poorly incorporated (0.0064%) into berberine, and although ( + )-tetrahydroberberine was efficiently incorporated (8.9%), the ease with which it undergoes autoxidation to berberine makes interpretation of the result difficult. However, (— )-tetrahydroberberine [(— )-canadine], having the same absolute configuration as (4- )-reticuline, does occur in H. canadensis, and its isolation from a feeding experiment with labeled reticuline showed it to be radioactive (0.035% incorporation). Nevertheless, the demonstration... 

Berberine and 8-cyanodihydroberberine were found to exhibit significant activity (> 50% suppression of lesion size) against the lesions of Leishmania braziliensis panamensis in golden hamsters. Tetrahydroberberine (canadine) was more potent but less toxic than berberine against Leishmania donovani, but not as potent as meglumine antimonate, a standard drug utilized in the therapy of leishmaniasis [209]. 

Another example is the simultaneous determination by LC—MS of seven active compoimds in a plasma sample collected after oral administration of a Zi-Shen pill (ZSP) xanthone glycosides (neo-mangiferin and mangiferin), timosaponins (timosaponin El, tim-osaponin B-11 and timosaponin B), and two alkaloids (palmatine and berberine) [23]. Ginsenoside Re (for xanthones and timosaponins) and tetrahydroberberine (for alkaloids) were chosen as internal standards (IS) for MS quantitation. Sample preparation consisted of only protein... 

It is of interest in this connection to note that the conversion of tetrahydroberberine into an anhydro-base of type E (p. 337) represents transformation from the berberine to the cryptopine type (p. 295), and that a-canadine methochloride occurs in Zanthoxylum brachyacanihum with its cryptopine analogue, y-homochelidonine ( -aiiocryptopine, p. 301). 

Berberine has been converted into a mixture of a- and /3-hydrastines, in the proportions 1 2 oxidation with potassium ferricyanide produced dimeric oxy-bisberberine, which with methanolic hydrochloric acid yielded the betaine (91). Hydration of this, followed by N-methylation, yielded the keto-ester (92), which gave a- and /3-hydrastines on reduction with sodium borohydride and subsequent hydrolysis.100 The photo-oxidation of tetrahydroberberine methiodide to allo-cryptopine has been reported.101... 

The chiroptical properties of the tetrahydroberberine alkaloids in relation to their absolute configurations have been studied.139 The pharmacokinetics140 and intercalative binding141 of berberine, the antipsychotic properties of tetrahydro-... 

Figure 2.6 Biosynthesis of berberine from (5)-reticuline in Berberis species and Coptis japonica. BBE, berberine bridge enzyme SCMT, (5)-scoulerine-9-0-methyltransferase CAS, (5)-canadine synthase STOX, tetrahydroberberine oxidase COX, enzyme found in Coptis japonica.

S)-canadine can act as a substrate for the tetrahydroberberine oxidase (STOX) enzyme isolated from Berberis and may be converted by this enzyme to berberine (Zenk, 1995) however, the oxidase found in Coptis japonica (COX)... 

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]. 

Several alkaloids based on the isoindoloisoquinoline, isoind-olobenzazepine, isoindolobenzazocine and isoquinolinobenzaze-pine skeletons have been discovered. In all of these except two the aromatic substitution pattern is the same as that in tetrahydroberberine, the exceptions being related to tetrahy-dropalmatine. They are assumed to be derived from alkaloids of the berberine series, from which some transformations have been effected. 

In recent years, attention has been paid to the physicochemical properties of the tetrahydroberberine and berberine alkaloids. Three papers have appeared on mass spectrometry of those alkaloids (655-657) and their N-methohalides 658). The mass spectra of 9-methoxytetrahydroproto-berberines show an intense peak which arises by cleavage of the methoxyl... 

Occurrence. Worenine Avas isolated from Coptis japonica (164). The base was separated from coptisine by virtue of the greater solubility of its nitrate or sulfate in alcohol or hot water. Worenine, mixed with berberine, Avas thus separated from coptisine, and reduction of this mixture afforded a separable mixture of tetrahydroberberine and tetrahydroworenine, the latter, C20H19NO4, melting at 212-213°. 

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. 

---