1-Bisbenzylisoquinoline alkaloids

The bisbenzylisoquinoline alkaloid tubocurarine would be an obvious goal for biotechnological production. However, to our knowledge no reports on cell cultures of Chondodendron tomentosum, the plant from 

Patents on Production of Cephalotaxus Alkaloids by Means of Plant Cell 

SEC of Agriculture. US 4152-214. 07-10-1977-US-840423 (01-05-1979). Preparation of cephalotaxine and related antitumor alkaloid(s) by cultivation of Cephalotaxus harringtonia tissue in nutrient medium. 

Kyowa Hakko Kogyo KK. J5 7102-194. 17-12-1980-JP-177122 (25-06-1982). Cephalotaxine and ester(s) production by subjecting plant cells to liquid culture. 

Berberis cell cultures were also reported to produce bisbenzylisoquino-line alkaloids. Cassels et al. 412) screened 34 callus cell lines (33 species). In all cases the protoberberine alkaloid Jatrorrhizine was the major component in aU but 12 cell lines bisbenzylisoquinoline alkaloids were found. High levels of berbamine were found in B. angulosa (0.8% of dry weight) and B. henryana (0.48%). Berbamunine (16) and the new alkaloid 2-norberbamunine (17) were the major alkaloids in B. stolonifera cell lines 

Bisbenzylisoquinoline Alkaloids.—The biosynthesis of several bisbenzyl-isoquinolines has now been investigated. All have been found to be based on coclaurine (bS). Investigation of the biosynthesis of oxyacanthine (69), in Cocculus laurifolius, has given results which show that this alkaloid too arises from coclaurine. Norcoclaurine (62), coclaurine (63), and N-methylcoclaurine were 

Ipecac Alkaloids.— The stereochemistry of ipecoside (71) is known by X-ray analysis, and this has been confirmed. Feeding experiments in Cephaelis ipecacuanha have given results which demonstrate that it is not desacetylipecoside (72), as previously supposed cf. ref. 2), but desacetylisoipecoside (73), with the same stereochemistry at C-1 (= C-llb) as cephaeline (76) and emetine (75), which is the true precursor for these alkaloids. Similar results were obtained for cephaeline (76) in Alangium lamarckii On the other hand, desacetylipecoside (72), and not (73), is the precursor for ipecoside (71) (in C. ipecacu- 

Bisbenzylisoquinoline Alkaloids.—The biosynthesis of a number of bisbenzyl-isoquinoline alkaloids has been investigated (cf Vol. 11, p. 11 Vol. 10, p. 16 Vol. 9, p. 11). Appropriate to the oxygenation patterns of the alkaloids examined, they have all been found to derive through coclaurine (48), and also, in some cases, iV-methylcoclaurine (49) e.g., tiliacorinine (50) in Tiliacora racemosa44 (cf. Vol. 9, p. 11). The biosynthesis of nortiliacorinine A (51), produced by the same plant, has been investigated and found to be from two molecules of coclaurine (48).45 

It may be noted that results with the various precursors neatly allowed the structure of tiliacorinine A (51) to be clarified and the stereochemistry at the two asymmetric centres to be defined.45 It is interesting that the right-hand half of (51) does not form from TV-methylcoclaurine (by demethylation), unlike the similar A-methylated fragment in (50), which has the opposite stereochemistry at C-l.  

Tetrandrine (52) has been shown46 to be formed in Cocculus laurifolius from two molecules of (+)-(S)-A-methylcoclaurine [as (49)1, a natural constituent of this plant (cf. the biosynthesis of the isomeric isotetrandrine in Vol. 11, p. 11). 

Several bisbenzylisoquinolines that are found in Berberis species of northern Pakistan can be derived, formally at least, from the naturally occurring spiro-dienone alkaloid pakistanamine (54).48 It is notable that the relative abundance of alkaloids derived by formal dienone-phenol rearrangement in (54) by mechanism (a) is greater than that of more hindered alkaloids formed by mechanism (b). 

Bisbenzylisoquinoline Alkaloids.—The skeleton of coclaurine (46) is one which serves as a common starting point for the biosynthesis of several bisbenzylisoquinoline alkaloids (cf. Vol. 10, p. 16). Coclaurine (46) and JV-methyl-coclaurine (47) have recently been found to be precursors also for isotetrandrine 

Bisbenzylisoquinoline Alkaloids.—Until recently, the biosyntheis of only one of the many bisbenzylisoquinoline alkaloids had been studied. This was episte-phanine (57), shown to derive from two units of coclaurine (59). New results establish that several other bisbenzylisoquinolines are variations on the coclaurine theme too. 

The diastereoisomeric bases tiliacorine and tiliacorinine (61) have been found to incorporate radioactivity from tyrosine, norcoclaurine (58), coclaurine (59), and N-methylcoclaurine (60) in Tiliacora racemosa the fully methylated isoquinoline, as to be expected, was not utilized for biosynthesis. Degradation of 

These results firmly point to the derivation of tiliacorine and tiliacorinine from N-methylcoclaurine (60), and it is clear that the coupling of the two units is stereospecific. A final piece of evidence confirms the biosynthetic role of (60) it was isolated in a trapping experiment after feeding radioactive tyrosine. It is thus a normal constituent of T. racemosa. 

The biosynthesis of cocsulin (63) and cocsulinin (64) in Cocculus laurifolius has been found to parallel that of tiliacorine and tiliacorinine (above). Thus bpth are formed from two units of iV-methylcoclaurine (60), without iV-demethylation [coclaurine (59) and norcoclaurine (58) were also incorporated an incorporation 

Tiliagenine (66) has also been shown to derive from A/-methylcoclaurine (60), the (+) — (5)-isomer providing one half of the molecule, with the other arising from (-)-(/ )-N-methylcoclaurine the configurations at C-1 and C-T could be deduced as (5) and (R), respectively.  

5 Bisbenzylisoquinoline Alkaloids. — The biosynthesis of a number of bisbenzyl isoquinoline allcaloids has been investigated (cf. Vol. 12, p.ll Vol. 10, p.l6 Voi. 9, p.ll). One of these investigations concerned tiliacorine and tiliacorinine. The 

Preliminary results using Thalictrum minus which showed that thalicarpine (41) was formed from two molecules of reticuline 

The results are supported by those of other workers obtained with 3 8 

Cocculus laurifolius. Of several related isoquinolines tested, 

It follows that a demethylation occurs at some point 

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Coclaurine is of special interest since worcoclaurine (I MeO HO) can be regarded as the parent substance from which by ether formation the series of bisbenzylisoquinoline alkaloids can arise. Thus, the dauricine type of alkaloid may be formed by a single ether linkage between the 4 -hydroxyl of one woreoclaurine molecule and a hydrogen atom ortho to the 4 -hydroxyl of a second molecule. 

Bisbenzylisoquinoline alkaloids are dimeric benzyltetrahydroisoquinoline alkaloids that are known for their pharmacological activities. A well-described example is the muscle relaxant (+)-tubocurarine, which in crude form serves as an arrow poison for South American Indian tribes. In the biosynthesis of this broad class of dimeric alkaloids, it has been postulated that the mechanism of phenol coupling proceeds by generation of phenolate radicals followed by radical pairing to form either an inter- or intramolecular C - O or C - C bond. Enzyme studies on the formation of bisbenzylisoquinoline alkaloids indicated that a cytochrome P-450-dependent oxidase catalyzes C - O bound formation in the biosynthesis of berbamunine in Berberis cell suspension culture.15 This enzyme, berbamunine synthase (CYP80A1), is one of the few cytochromes P-450 that can be purified to... 

Fig. 10.3 Reaction catalyzed by the cytochrome P-450-dependent oxidase berbamunine synthase (CYP80A1). This enzyme creates a branchpoint in the (5)-reticuline biosynthetic pathway to form the bisbenzylisoquinoline alkaloids.

Otshudi, A. L., Apers, S., Pieters, L., Claeys, M., Pannecouque, C., Clerq, E. de, Van Zeebroeck, A., Lauwers, S., Frdddrich, M. and Foriers, A. 2005. Biologically active bisbenzylisoquinoline alkaloids from the root bark of Epinetrum villosum. Journal of Ethnopharmacology, 102 89-94. 

Leclerq, J., Quetin, J., De Pauw-Gillet, M.-CL, Bassleer, R. and Angenot, L. 1987. Antimitotic and cytotoxic activities of guattegaumerine, a bisbenzylisoquinoline alkaloid. Planta Medica, 116-117. 

Kuroda, H., Nakazawa, S., Katagiri, K., Shiratori, O., Kozuka, M., Fujitani, K. and Tomita, M. 1976. Antitumor effects of bisbenzylisoquinoline alkaloids. Chemistry and Pharmacology Bulletin, 24 2413-2420. 

Although it is almost a cliche to point out the ever-accelerating pace of scientific development, since the last review on the bisbenzylisoquinoline alkaloids in... 

The format follows that of the earlier review. The subject of synthesis, however, which formerly constituted a separate chapter, is included in this work, and other coverage has been expanded, particularly in the areas of plant biochemistry and pharmacology. The tabulation of all known bisbenzylisoquinoline alkaloids has been revised and updated. A section listing other major review articles on these alkaloids is also included, and the reader may wish to consult some of these for extensive physical data. In keeping with the original purpose of this treatise, we have tried for a comprehensive overview, with strong emphasis on the specific chemistry of the bisbenzylisoquinoline alkaloids, rather than an exhaustively detailed presentation. 

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