Dimeric alkaloid

As noted, the alkaloid yield from the Beocin plants was low, which the authors suggested might be caused by the poor soil in which the plants were growing (Popovic et ah, 1992). One could ask whether the soil conditions to which they refer might be influential in the overall alkaloid biosynthetic processes in this species. It would be of interest to see experimental studies aimed at determining the effect of soil components on these processes. In the present case, it may be a lack of, or reduction in the activity of, the oxidase(s) necessary for the dimerization process (required to form the bibenzyldihydroisoquinolines) to occur. It is also possible that the lack of dimeric alkaloids may simply reflect a concentration effect caused by the edaphic conditions. These questions should be accessible to experiment. 

Fig. 12.1. Predictive model for enantioselective dihydroxylation by dimeric alkaloid catalysts. (DHQD)2 catalysts give (3-approach (DHQ)2 catalysts give ot-approach. Reproduced from J. Org. Chem., 57, 2768 (1992), by permission of the American Chemical Society.

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... 

In addition to monomeric capuronine (159), capuronidine (170), and other dimeric alkaloids, Husson et al. isolated from T. capuronii (Capuronetta ele-... 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

It is probably not by chance that the only true dimeric alkaloids to have been found till now in the Coccinellidae originate from Psylloborini species, but it is too early to draw any chemotaxonomic conclusions from these data. 

Though these alkaloids are not truly composed of two identical monomeric units, they are popularly named dimers or dimeric alkaloids. We prefer to avoid this incorrect nomenclature and would like to encourage the use of the more adequate binary terminology. In another consideration of nomenclature, we describe quaternary salts derived from an imine functionality as imonium salts, in accord with the descriptor for other onium salts (ammonium, oxonium, etc.), rather than by the frequently used iminium terminology. This nomenclature was suggested earlier (/). 

Zhalolov, 1. Z., Khuzhaev, V. U., Levkovich, M. G., Aripova, S. F. and Shashkov, A. S. 2002. Alkaloids of Arundo donax. XL NMR spectroscopic study of the structure of the dimeric alkaloid arundamine. Chemistry of Natural Compounds,... 

Vinca dimer indole alkaloids (e.g. vinbiastine) act as spindle poisons. They bind tubulin, inhibiting polymerisation into microtubules, the major elements of the cytoskeleton [100]. Vinblastine itself and its analogue vinoreibine (Navelbine ) [101] are marketed for cancer therapies (Fig. 36). Vinflunine (Javlor ) is a member of second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinoreibine in several cancers (Fig. 36). It is now in phase III clinical... 

Fig. 36. Anti-mitotic drugs derived from Vinca dimer alkaloids.

The structure [225] has been assigned to a dimer alkaloid of 6,7/5-oxidodeoxynupharidine. (151) On changing solvent from CDC13 to... 

Acetylation of phenolic functions produces predictable effects on adjacent aromatic protons. For example, the assignment of the OH groups of thalictroga-mine (429) to C-l and C-7 was based on an upfield shift of H-ll and a downfield shift of H-8 in the diacetate (209). The NMR shifts of the C-8 hydrogen in several bisbenzylisoquinoline-aporphine dimers have been summarized (295). H-NMR spectra of some bisbenzylisoquinoline and related dimeric alkaloids have been tabulated (296,297). 

H. Guinaudeau, M. Leboeuf, and A. Cav6, J. Nat. Prod. 47,565 (1984). Dimeric aporphinoid alkaloids. Cites 23 new dimeric alkaloids and 8 related synthetic derivatives for 1979-1984 48 references. 

The first dimeric quinoline alkaloid, pteledimerine, was isolated recently from the root bark of Ptelea trifoliata (cf. Vol. 10, p. 80). Several related compounds have now been found in the same species, and the structure of one of them, pteledimeridine (16), was elucidated mainly by means of H n.m.r. and mass spectroscopy.9 The two dimeric alkaloids are isomeric and differ only in the nature of the furoquinolone portion, which has angular annelation (2-quinolone) in pteledimeridine and linear annelation (4-quinolone) in pteledimerine. 

The presence of isoretulinal (111) in the root bark of Strychnos variabilis de Wild, has been confirmed,79 and it has also been shown that retulinal (112), with which it is very easily equilibrated, occurs in smaller amounts in the same extracts both alkaloids exist in two forms, which are amide rotamers, according to their n.m.r. spectra. The 12-hydroxy-derivatives, (113) and (114), form a similar equilibrating pair of alkaloids, and were also isolated from this source. The occurrence of these easily interconvertible C-16 epimers explains the simultaneous occurrence of retuline and isoretuline derivatives in Nature, in both the monomeric and dimeric alkaloid series. 

Transformations of the dimeric alkaloid vinblastine (46) by Streptomyces species have been reported which involve N-demethylation (51), aromatic hydroxylation (55), and intramolecular ether formation (53). With Streptomyces albogriseolus, N-demethylation occurs in an undisclosed yield to produce 47 (51). The same organism in the hands of the same workers is also reported to lead to the formation of vinblastine ether (50) in low yield, along... 

A partial synthesis101 of alstonerine (178) from macroline (179) (shown in Scheme 17) is of considerable interest, in view of the strategic position occupied by macroline as a possible precursor of both the monomeric Alstonia alkaloids (e.g. alstonerine) and the dimeric alkaloids (e.g. villalstonine and macralstonine). 

Northalicarpine (61), which is present in Thalictrum revolution, is the first known noraporphine-benzylisoquinoline dimer.29 Berberis orthobotris has also furnished two known dimeric alkaloids, pakistanamine (60) and pakistanine.67 Thalicarpine has been re-isolated from Thalictrum alpinum,42 Cancer patients showed no objective response when treated with this alkaloid.71... 

The absolute configuration of (-t-)-macroline, obtained by degradation of the dimeric alkaloid villalstonine, follows70" from its transformation into a mixture of the tetracyclic base (138) and its C-20 epimer. Base (138) was also obtained by degradation of ajmaline (139), as outlined in Scheme 21 the C-20 epimer of (138) was similarly obtained from isoajmaline, which is epimeric with ajmaline at both C-20 and C-21. 

Gonopharyngia durissima has afforded iboga bases, two dimeric alkaloids discussed under Voacanga alkaloids, and a trace of a base, alkaloid E, mp 191°-193°, pif a 7.26, UV-maxima at 210 and 305 mp, which differed from the other isolates in having no carbonyl absorption in the IR-spectrum (14). Gonopharyngia pachysiphon, in contrast to C. durissima, has yielded only steroidal bases (45). 

A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12. They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea (= Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the Aa-formyl analog, CIV, forms part of the dimeric alkaloid leurocristine (5, 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V. rosea and its dihydro-decarbomethoxy derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpa species (53). ( + )-Vincadif-formine (XCIII, 6, 74) has already been mentioned as the racemic form of (— )-6,7-dihydrotabersonine (Section II, O). It has been found in V. difformis and in Rhazya stricta (51b) where the (+) form also occurs. 

The quaternary C-alkaloid D was first isolated (16) from a sample of calabash curare and was later encountered (24) as one of the products formed when C-dihydrotoxiferine I is treated with dilute acid in the presence of oxygen. Because of its low mobility on paper chromatograms, it was considered to be a dimeric alkaloid, and the formula C4oH48N4Or was proposed (116) on the basis of analyses of the several crystalline salts afforded by this alkaloid. Despite its bisquaternary nature, C-alkaloid D has a low curarizing activity, and in this respect it is similar to caracurine V dimethochloride mentioned earlier. C-Alkaloid D chloride shows [a]D — 51° (in 1 1 aqueous acetone). 

In a pair of back-to-back papers, the author and co-workers first reported the isolation and characterization of thalibealine (70), a novel tetrahydro-protoberberine-aporphine dimeric alkaloid from Thalictrum wangii,143 That report was followed by a paper reporting the synthesis of thalprezwalskinone (71) and a revision of the structure of that alkaloid.144... 

Regarding the 1,3-diazocines, it was reported that the synthesis of the left domain of haplophytine, a hetero-dimeric alkaloid endowed with insecticidal activity, contained a pyrrolo-fused carbonyl bridged 1,3-benzodiazocine moiety <2007AG(E)4715>. It was also reported that the synthesis of a pyrazolo-fused 1,3-benzodiazocine and its activity as inhibitor of lymphocyte-specific protein tyrosine kinase (Lck) <2007W0026720>, and the thermal decomposition of a polynitro substituted 1,3-diazocine <2006RJGC499>. 

---