Protoberberine alkaloids, berberine

Fig. 22D MaJioniae radix/cortex (4) is characterized in the R, range 0.4.5-0.5 by the four yellow-green fluorescent protoberberine alkaloids berberine (Tl) and jatrorrhizine (T4) a,s well as columbamine (T5) and palmatine (T8). Magnofiorine is seen as a dark zone at R,- 0.2...

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. 

N.A. Berberis aquifolium L. Berberine, protoberberine alkaloids, oxyberberine, magnoflorine, columb amine.1 °°.273 -274 For eczema, gall bladder disorder, chronic hepatitis B, gastritis, diarrhea, antipsoriasis. 

Protoberberine Alkaloids.—In the course of the bioconversion of the proto-berberine scoulerine (65) into chelidonine (62) and phthalide-isoquinolines, e.g. narcotine (63), C-13 becomes oxidized.61 Ophiocarpine (68), with a hydroxy-group at C-13, represents an intermediate stage in the modification of the protoberberine skeleton, and results62 of tracer experiments have shown that scoulerine (65) is also to be included in the biosynthesis of this alkaloid. Tetrahydro-protoberberine (67) is also a precursor, its incorporation indicating that C-13 hydroxylation is a terminal step. As for other protoberberine derivatives,63 nandinine (64) was not assimilated,62 and it follows then that (65) is probably converted into (67) by way of isocorypalmine (66). 

It is known that berberine (46) and the protoberberine alkaloid (S)-stylopine (44) are elaborated from an intact molecule of (S)-reticuline [as (33)], the 7V-methyl group providing C-8 in each alkaloid1,2,42 (cf. Vol. 7, p. 12). Exactly similar findings were obtained for tetrahydropalmatine (45) and palmatine (47) in C. laurifolius.43 Of several benzylisoquinolines tested, only reticuline (33), nor-reticuline (41), and norlaudanosoline (40) were significantly incorporated. Tetrahydropalmatine (45) was found to be converted into palmatine (47) and the conversion was irreversible. 

S)-Reticuline is a branch-point intermediate in the biosynthesis of most BAs. Most work has focused on branch pathways leading to the benzophenanthridine (e.g., sanguinarine), protoberberine (e.g., berberine), and morphinan (e.g., morphine and codeine) alkaloids.19 Most enzymes involved have been isolated, many have been purified, and four corresponding cDNAs have been cloned.19 The first committed step in benzophenanthridine and protoberberine alkaloid biosynthesis involves the conversion of (S)-reticuline to (5)-scoulerine by the berberine bridge enzyme (BBE) (Fig.7.2). BBE was purified from Berberis beaniana,20 corresponding cDNAs were cloned from E. californica and B. stolonifera,21 22 and BBE genes have been isolated from P. somniferum and E. californica.23,24... 

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)... 

Berberine bridge enzyme catalyses are specialized step in protoberberine alkaloid biosynthesis similar genes and proteins are, however, widely present in higher plants, indicating common ancestry (Fig. 7.17c). BBE or similar proteins, which share a number of common conserved sites (Table 7.8), could also be found in fungi and bacteria. A similar pattern can be seen in the distribution of CR (Fig. 7.17d, Table 7.9). 

This alkaloid has been isolated recently in very small yield from the much investigated plant, Hydrastis canadensis L. (57). Analysis of the iodide indicated the molecular formula C20H18O5N I . It contains two methoxyls and a methylenedioxy group, one hydroxyl function, and is optically active ([a]D+107°). The UV-spectrum of berberastine is typical of a protoberberine alkaloid and its near relationship to berberine was suggested from its IR-spectrum which, apart from the presence of hydroxyl absorption, closely resembled that of berberine iodide. 

Speculations on the biosynthesis of berberine date back to the beginning of the century (121). Most of the early proposals recognized the structural relationship of the protoberberine alkaloids with the simpler benzylisoquinoline bases, from which it was supposed that they are derived. The additional carbon atom necessary for the formal conversion... 

The foregoing results are in consonance with the ideas proposed many years ago by Robinson and others, and are best interpreted as tyrosine giving rise to 3,4-dihydroxy-2-phenylethylamine and 3,4-dihydroxy-phenylacetaldehyde which condense to form the 1-benzylisoquinoline intermediate, norlaudanosoline. Insertion of the C-1 unit of the berberine bridge would then complete the skeleton of the protoberberine alkaloids. 

Administration of triply, 3C-labelled (5)-reticuline to a stable variant non-alkaloid producing cell culture line of Thalictrum tuberosum in cell culture demonstrated a very high incorporation of label into protoberberine alkaloids that were subsequently produced. Since this cell line does not produce reticuline, because the cell line lacks or has insufficient quantities of three methyltransferases that lead to the formation of reticuline, cell cultures that contain this cell line are appropriate for the study of biosynthetic studies., 3C NMR spectroscopy and CIMS were utilized to follow the time course of the metabolism, and demonstrated the rapid formation of scoulerine as a primary reaction product, followed by further tetrahydroprotoberberines and dehydroprotoberberines. The apparently reversible formation of dehydroscoulerine in significant amounts was interpreted as evidence for the role of this compound as an alkaloidal storage product from which scoulerine may be regenerated via enzymic reduction. Scoulerine, dehydroscoulerine, columbamine, and (S)-reticuline were detected by l3C NMR in the crude extracts, while berberine was detected by HPLC. The biosynthetic pathway of these protoberberines in this variant cell culture were summarized as follows [151] (S)-reticuline > scoulerine -> tetrahydrocolumbamine (hypothetical) -> columbamine -> dehydroscoulerine -> candadine -> berberine. 

Berberine chloride was evaluated for antimalarial activity against Plasmodium falciparum in vitro (two clones of human malaria Plasmodium falciparum D-6 [Sierra Leone clone] and W-2 (Indochina clone) and Plasmodium berghei in vivo (mice). The alkaloid exhibited an antimalarial potency equivalent to that of quinine in vitro, but was inactive in vivo. The results were consistent with those of others who have found berberine to be a potent inhibitor in vitro of both nucleic acid and protein biosynthesis in P. falciparum, and have demonstrated a strong interaction of berberine with DNA. In addition, the lack of in vivo antimalarial activity in mice observed with berberine and other protoberberine alkaloids agrees with clinical reports that have claimed berberine to be inactive as an antimalarial drug [228]. 

Four protoberberine alkaloids and one aporphine alkaloid were evaluated for lipoxygenase inhibition. Oxyberberine and columbamine were the most potent lipoxygenase inhibitors tested, with jatrorrhizine being intermediate, whereas berberine and magnoflorine exhibited only low potencies. A strong linear correlation between lipoxygenase inhibition and lipid antioxidant properties of these alkaloids was observed. These data suggest that the mechanism of... 

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