Bisindole

Bisindole Alkaloids from Tryptophan. There are two widely different types of alkaloids derived from two tryptophan (26) units. The first is a rather small group of compounds based simply on the dimers of tryptophan which includes compounds such as calycanthine (113) (Table 10),... 

The search for the bisindole derivatives (22) was originally (81) initiated on the basis of folklore. A brew made from Jamacian periwinkle had estabhshed itself in local medicine as a treatment for diabetes and it was this material that was investigated and found to contain the cytotoxic compounds (22), among others. No materials useful in the treatment of diabetes have been reported from this source. 

An international team of experts review the whole field of alkaloid chemistry This volume contains three special non recurrent reviews on bisindole alkaloids, the biosynthesis of terpertoid indole alkaloids, and on pharma -cologicalty interesting ar>d chemically useful alkaloids it covers the period January 1969 to Jur>e 1970. 50Spp til 00... 

From a commercial viewpoint the most important compounds of this class are the 3,3-(bisindol-3-yl)phthalides. The first synthesis47 involved Route B as described in Scheme 7, in which a second indole derivative condenses with the indolylbenzoylbenzoic acid in acetic anhydride. However, for the preparation of symmetrical derivatives it has been shown61 that a one-pot process, avoiding isolation of the intermediate and use of aluminum chloride, is more convenient. 

Although 7,14-dihydroxy-6H,13H-pyrazino[l,2- 4,5-,T]bisindole-6,13-dione can jn pr ncipie exist in two tautomeric forms of the dihydroxy compound 39 and the diketo form 40, only the dihydroxy is observed <2003OBC3396>. Presumably this is due to the enolizable 1,3-dicarbonyl moieties and the formation of the indole ring, therefore leading to aromaticity and a net overall stabilization. 

In addition to monomeric compounds, Tabemaemontana plants contain many bisindole alkaloids that are classified on the basis of constituent monomeric units, as in the extensive review by Cordell and Saxton in Volume XX of this series (14). This classification is more rational and comprehensive than others (I, 13, 15) and will be used as a guide for the representation of structural formulas and for the discussion of the chemistry of single alkaloids. 

The great number of different alkaloids found in Tabemaemontana precludes a discussion of the structure elucidation and chemistry of all of them. To keep the treatment concise, a major compromise was necessary. The alkaloids that have been reported in previous volumes of this treatise (as indicated in Table I) and their trivial modification will not be mentioned here. This compromise eliminates from the discussion well-established and long-known alkaloids that were isolated not only from Tabemaemontana but also from other genera. Moreover, the plumeran alkaloids isolated up to 1976 and ebuman-type and bisindole alkaloids isolated up to 1979 are covered in Volumes XVII and XX. The main efforts of this chapter will be focused on more recently isolated compounds, some of which are structurally and biogenetically relevant and have been found only in plants of the genus Tabemaemontana. 

Achenbach and Schaller have reported the isolation from the root bark of T. accedens of three monomeric alkaloids in addition to several bisindole alkaloids... 

E. Bisindole Alkaloids 1. Corynanthean-Aspidospermatan-Type Alkaloids... 

From 250 g of root bark of T. chippii, a small tree growing in the high forest or bush and occurring in the Ivory Coast and Ghana, nearly 4 mg of the new bisindole alkaloid vobparicine (200, C39H43N402) were isolated (62). The dimeric nature of this compound suggested by the molecular formula was con-... 

Ervafoline did not fragment under the acidic conditons used for the cleavage of other bisindole alkaloids. The complete structure and relative stereochemistry of ervafoline, as shown in formula 246, were determined by a single-crystal X-ray study. 

From the leaves of Pandacastrum saccharatum, a species of the Apocynaceae now classified under Tabernaemontana, Das et al. isolated a novel bisindole... 

Another cultured cell line of Catharanthus roseus (EU4A), which does not produce detectable amounts of vinblastine and other bisindole alkaloids, was also examined for its ability to transform 78 (183). Cell-free extracts of the culture line were prepared, and the 35,000 X g supernatant solution was used. Incubations with 2r-tritioanhydiovinblastine yielded a mixture from which radioactive vinblastine (52) was isolated. The labeled vinblastine was reisolated after unlabeled carrier was added and rigorously purified by successive thin-layer chromatography, reversed-phase HPLC, and crystallization to constant specific activity. Boiled extracts could not produce labeled 52, thus supporting the involvement of enzymes in the conversion process. 

The same authors then studied the formation of ternary complexes with cahnoduhn, TFP and two bisindole drug molecules vinblastine and KAR-2 (structures shown in Figure 6.25) using the near-UV CD method. They found that both TFP and KAR-2 are able to bind to calmodulin simultaneously forming a ternary species but that vinblastine is not able to bind to a TFPiCaM complex. If the CD experiment was repeated under conditions in which the... 

ISOLATION, STRUCTURE ELUCIDATION, AND BIOSYNTHESIS OF THE BISINDOLE ALKALOIDS OF CATHARANTHUS... 

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. 

There are two generally accepted numbering systems for the bisindole-type alkaloids. The system used throughout the chapter is shown around formula 1 however, the biogenetic numbering system presented for vinblastine as formula lA is still in wide use. 

The occurrence of structurally established bisindole alkaloids in Cath-aranthus roseus (L.) G. Don and in the minor species of Catharanthus, namely, C. lanceus (Boj. ex DC.) Pich., C. longifolius Pich., C. ovalis Mgf., C. pusillus (Murr.) G. Don, and C. trichophyllus (Bak.) Pich, is... 

Bisindole Alkaloids with Established Structures Isolated from Catharanthus Species... 

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