Indole alkaloids, dimeric

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

Because of the previous inaccurate botanical determination of the Madagascan periwinkle, the alkaloids of this plant were formerly considered as Vinca alkaloids, an erroneous subclassification for alkaloids isolated from a plant belonging to the genus Catharanthus. It also should be noted that the alkaloids of C. roseus containing two different (most commonly indole and dihydroindole) alkaloid building blocks were, and sometimes still are, referred to as dimeric indole alkaloids. It is more accurate to use the term binary or bisindole alkaloids, since chemically these alkaloids are not dimers of two equal subunits, but rather comprised of two (bis) different alkaloid building blocks. 

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... 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

N.A. Alkaloids, tannins, saponins, pectin, oleoresin, aldehydes, dimeric indole alkaloids, vinblastine, sesquiterpenes.100114315 Treat diabetes, leukemia, reduce blood pressure, Hodgkin s disease, hypotensive, sedative and tranquillizing, anticancer. 

Dimeric indole alkaloids Diosgenin Dipentene Disulphides... 

Vincristine (26b) and vinblastine (26a) are representative of the so-called dimeric indole alkaloids which arise in the plant by combination of non-identical monomeric alkaloids. Vincristine in particular has important clinical activity both as a single agent and in combination chemotherapies (B-77MI30614). Recently, a semi-synthetic derivative vindesine (26c) in which the C-16 methoxycarbonyl group has been converted to a primary amide... 

Three dimeric indole alkaloids of a new type, peceyline, peceylanine, and pelankine, have been isolated from a Sri Lankan apocynaceous plant, Petchia ceylanica Wight.876 The structures of these bases were determined mainly by n.m.r. spectroscopy. In their H spectra, all three alkaloids exhibit four aromatic singlets, one olefinic hydrogen multiplet, two methoxycarbonyl singlets, two N-methyl singlets, and two C-methyl doublets. One half of the non-aromatic carbon resonances in the 13C spectra show that one monomer unit is common to all three alkaloids, and inspection reveals that this unit must be based on vincorine... 

Vinblastine (4 in Chart 1) and its congeners are dimeric indole alkaloids derived from Catharanthus (Vinca) roseus. Nowadays, the vinca alkaloids constitute an important class of widely and successfully used anticancer agents that inhibit tubulin polymerization [8],... 

Also the peroxidase involved in the biosynthesis of dimeric indole alkaloids is localized in vacuoles. For a discussion, see Sottomayor, M., de Pinto, M. C., Salema, R.,... 

The bisindole alkaloids alstomacrophylline 108 and alstomacroline 109 have been isolated from the root bark of Alstonia macrophylla along with the monomeric indole alkaloid 20- f-antirhine <1997P757>. A dimeric indole alkaloid, schischkiniin 110, was isolated from the seeds of Centaurea schischkinii <2005T9001>. 

Chimonanthine (172),242 isolated from leaves of Chimonanthus fragrans Lindle (Calicanthaceae), is an example of naturally occurring dimeric indole alkaloids of type C. 

The pseudophrynamines have not been detected elsewhere in Nature. In myobatrachid frogs of the genus Pseudophryne, they occur in varying amounts in all species examined (56). The pair of dimeric indole alkaloids, chimonanthine/calycanthine, have been detected in amphibians only in the dendrobatid frog Phyllobates terribilis and, tentatively, as a trace alkaloid in Phyllobates bicolor (14). 

Deoxytetrodotoxin, 264-265 3, 4 -Dideoxynorlaudanosoline-1 -carboxylic acid, 146-147 Dimeric indole" alkaloids, 261 L-Dopa, optically active... 

Scott AI, Gueritte F, Lee SL. Role of anhydrovinblastine in file biosynthesis of file antitumor dimeric indole alkaloids. J. Am. 

C.Martins, S. cmtdnaeana Wedd. and closely related species of the family Lo mia-cme is used. Among the many alkaloids that occur in these barks, toxiferine-I shonld be mentioned, a dimeric indole alkaloid (with strychnine-skeleton) which has two quaternary nitrogens. 

Alstonerine " from Alstonia muelleriana (82) is a structural type first recognised as one half of the dimeric indole alkaloid villalstonine. The oxindole analogue pf this structural type has been known for some time. 

One of the newer groups of indole alkaloids is that of the bisindole alkaloids or dimeric indole alkaloids as they are commonly called, although in only very few instances is the term dimeric strictly applicable. Under the heading Bisindole Alkaloids we include those natural products which are clearly comprised of two individual units which in the strict sense would be classed as indole alkaloids in their own right. More than eighty such products have been reported to date, but although a number have been known for many years, actual structural elucidation gCes back only twelve years. This fact clearly demonstrates that without the recent rapid development of separation and analytical techniques this particular field would have remained virtually unopened. 

Bisindole alkaloids (103), sometimes known as dimeric indole alkaloids, are composed of two identical or different monomeric indole alkaloid units... 

Lastly, beside monoindole, four dimeric indole alkaloids of the reticuline-diaboline type have been isolated from the root bark of Strychnos panganensis two couple of stereoisomers on C-19 or C-19 named panganensine R (30) and S (31), and panganensine X (32) and Y (33) respectively [33]. It has not been possible to assign the C-19 configuration for 32 and 33. 

The ultimate goal of the syntheses of compounds with the Aspidosperma nucleus is vindoline (101). One component of many of the dimeric indole alkaloids of Catharanthus roseus, vindoline (101) is a structural component of vincaleukoblastine, the powerful oncolytic agent, and N-demethyl-N-... 

Tabernaemontana cell cultures have also been studied as a source for dimeric indole alkaloids (for review, see Ref. 730). Although the plants produce considerable amounts of dimers, so far only small amounts of conodurine-type dimers and monogagaine could be found in callus cultures of T. elegans (731). Cell suspension cultures of this species produced various monomers, whereas only traces of yet unidentified dimers could be found (732). 

Amauromine, a dimeric indole alkaloid with hypotensive vasodilator properties, was isolated from Amauroascus species (Gymnoascales, Ascomycotina) (267) and Penicillium verrucosum (26S). The structure of this metabolite was determined by chemical and spectroscopic investigations and confirmed by a total synthesis by Takase et aL 268). The symmetrical diketopiperazine made up of two modified tryptophans, each bearing a 1,1-dimethylallyl group at C-3, was synthesized as shown briefly in Scheme 45. The two inverted prenyl groups were introduced simultaneously by a thio-Claisen rearrangement reaction through the sulfonium salt. 

Although, by inspection, it would seem probable that the dimeric indole alkaloids, such as vinblastine (104), have their genesis in monomeric bases, such as vindoline (89) and catharanthine (90), investigations have been dogged by poor incorporations cf. ref. 9. Most recently, however, even more careful work and the employment of cell-free preparations has given positive results. 

Polonoeski reaction (2, 7 5, 3). The first synthesis of the dimeric indole alkaloid vinblastine (4), used in the treatment of lymphomas, involved coupling of two indole units using a Polonovski reaction. Thus reaction of the N-oxide (1) and vindoline (2) with trichloroacetic anhydride afforded the quaternary im-monium compound (3), which was converted into (4) by standard methods (reduction with NaBH, rcacclylalion). ... 

C46HjgN40 Mr 810.99, cryst., mp. 216°C, [alp +42 (CHCI3) a dimeric indole alkaloid from Catharanthus roseus (see Vinca alkaloids), composed of two parts vindoline and catharanthine with a 10,3 -linkage. V. is a cytostatically active trace alkaloid and is accompanied by demethylated, deformylated, and deacety-lated alkaloids. V. also occurs in other Catharanthus species such as C. ovalis. C. longifolius, C. trichophyl-lus. It is one of the most important monoterpenoid indole alkaloids. 

---