Bisindole-type alkaloids

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. 

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

Tabernaemontana divaricata (double flower variety) provided an unusual minor alkaloid, voaharine (178), whose structure was established by X-ray analysis [137]. Voaharine is exceptional in being in all probability a tryptamine and jccologanine derived alkaloid but possessing a 3-quinolone instead of an indole chromophore. Voaharine is probably derived from voaphylline (180) (which is also present in the plant) via oxidation and rearrangement and represents the first instance of a 3-quinolone-type alkaloid obtained from Tabernaemontana. Besides these, and the known alkaloids N-methylvoaphylline (181), pachysiphine (tabersonine-P-epoxide) and apparicine, as well as two new bisindoles (vide infra), the plant also provided several new alkaloids of the aspidosperma-type including (-)-mehranine (179), voafinine (182), N-methylvoafinine (183), voafinidine (184) and voalenine (185) which were obtained in minute amounts [138-140]. 

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 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. 

Since the last major review of the biosynthesis of the monoterpenoid indole alkaloids (97), there have been several full and partial 98-104) reviews of various aspects of the work that has been conducted since 1974. Two major developments have dominated the field in this period, namely, the demonstrations that (i) strictosidine (33) is the universal precursor of the monoterpenoid indole alkaloids and (ii) selected cell-free systems of C. roseus have the ability to produce the full range of alkaloid structure types, including the bisindoles. This section traces some aspects of these developments, paying particular attention to work been carried out with C. roseus, and omitting work, important though it may be, on other monoterpenoid indole alkaloid-producing plants, e.g., Rauwolfia, Campto-theca, and Cinchona. 

Additionally, there had, for many years, been a vast synthetic effort underway aimed at the synthesis of the two monomeric units, where it was anticipated that the two units could be joined to form the vinblastine-type bisindole alkaloids. Coincidentally, as it transpired, 20 years of effort in the areas of synthesis and biosynthesis converged, at almost the same time, on the compound 3, 4 -anhydrovinblastine (8). 

The antiproliferative effects of bisindole alkaloids are well established. In general, these compounds are extremely toxic to a wide variety of cells in culture. The cytotoxic effects require a minimal exposure time approximately equal to the doubling time of the cells under test, usually 12 to 72 hr, at a drug concentration of 10 nM to 1 xM in order to achieve an ED, 8,9). Cell types that are characterized by short doubling times (e.g., lymphocytes) tend to be more sensitive than those cell types that divide more... 

Dividing cells in culture exposed to vinblastine or vincristine are arrested from further growth during mitosis (12,13). In fact, the antimitotic effects of this class of compounds is ubiquitous. These effects are observed at relatively low concentrations (<1 iM), and are reversible when drug is removed from the media prior to lysis of the arrested cells. The concentration of drug required to elicit an antimitotic effect is usually comparable to that required to produce a cytotoxic effect in the same cell type (14,15). Originally, this type of analysis was exceedingly laborious, but the introduction of laser- and computer-based fluoresence activated cell sorters (FACS) has rendered this type of analysis routine. Nevertheless, a cytotoxic, non-cell cycle-specific bisindole alkaloid has yet to be discovered. 

Peptide derivatives of the bisindole alkaloids have been prepared by appending amino acids at C-3. Reaction of acylazide 62 with an ct-amino acid ester affords amide derivatives of this type (122) (46). Conversely, the attachment of the amino acid can be inverted by reacting a C-3 amide derivative with an activated amino acid ester. Thus, treatment of 3-0-aminoethyl)-4-deacetylvinblastine amide (70) with an N-protected a-ami-noacylazide gives the alternative amide derivative (123). These techniques have been used to prepare di-, tri-, and tetrapeptide conjugates. 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

Another type of rearrangement ensues if the ATb-oxide (219) is treated with a nucleophile. This reaction can be applied to the partial synthesis of bisindole alkaloids (q.v.), but in most cases a by-product is obtained. In the simple example in which the nucleophile is acetate, the product obtained is the pentacyclic compound (222), in which the intermediate fragmentation product has cyclized on to Aa. Analogous compounds can also be obtained starting with dihydrocatharanthine or coronaridine. ... 

The popular garden plant Tabernaemontana divaricata which is extensively grown in gardens in Malaysia as well as in India provided several novel bisindoles, one of which, viz., conophylline (303) has been shown to be a potent inhibitor of ras functions (vide infra). There are two distinct varieties, the single flower variety produces both conophylline (303) and conophyllidine (304) [137,180] while the double flower variety gives in addition, a third dimeric alkaloid, conofoline (305) [ 138] as well as several new aspidosperma-type compounds. 

C NMR spectral data for 31 monomeric and 6 bisindolic alkaloids of the ajmaline type are presented in Table IV. 

On the basis of structure the dimers can be clearly divided into two groups. The first is comprised of alkaloids with identical or very closely related components in which the same centres act as linkage positions. The Calycanthaceous and Calabash-curare-South American Strychnos alkaloids make up this group. The second group consists of dimeric bases in which the alkaloid components are of a different structural type (e.g. geissospermine, vinblastine, and tubulosine) or in which two similar halves are linked unsymmetrically through two different centres e.g. macralstonine). The bisindole alkaloids will be discussed in this order. ... 

A characteristic of the genera Callichilia, Conopharyngia, Gabunia, Stemmadenia, Tabernaemontana, and Voacanga of the Apocynaceae family is the presence of bisindole alkaloids of the voacamine type, the prototype of this group being voacamine itself. All these alkaloids are composed of a vobasine-like [vobasine,... 

Some of the most difficult structural problems in the indole alkaloid field are associated with the bisindole alkaloids of the vobtusine type. Since 1955, vobtusine has been isolated on numerous occasions, often in large quantities, from the Apocynaceae species Callichilia, Conopharyngia, Rejoua, and Voacanga A correct molecular formula could only be determined by high-resolution mass spectrometry. In 1966 a partial structure was proposed for the alkaloid and later in the same year a complete structure was put forward. An unambiguous structural proof is, however, still lacking. The difficulty arises from the complete resistance of the alkaloid and its derivatives to cleavage, in contrast, for example, to the dimers of the voacamine and vinblastine types. Non-cleavable dimers occur also in calabash-curare but in these cases chemical correlation with cleavable alkaloids has been possible (see Section 2, p. 209). To date no bisindole alkaloid related to vobtusine has been found which can be split into monomeric units. 

Scheme 25 summarises the molecular ions to be expected from thermal inter-molecular transmethylation of a tertiary N(b>-atom. Such reactions have been investigated with simple model compounds. In the realm of bisindole alkaloids they were first observed with voacamine and vinblastine types. With the help of deuterium labelling it has been shown in the case of voacamine (141) (Section 9, p. 242) that the methyl group of the a-indolylacetic acid methyl ester function of the Iboga component is transferred to the N(b)-atom of the vobasinol component. An a-indolylacetic acid methyl ester is also present in the Vinca bisindole alkaloids (Section 10). It seems probable that the methyl transfer takes place in concert with decarboxylation to give the anion (290). The other methoxycarbonyl group is apparently not involved in methyl transfer. 

The majority of bisindole alkaloids which possess methoxycarbonyl groupings, other than of the above-mentioned type, e.g. villalstonine (213), pycnanthine (193), and vobtusine (255), show no significant methyl transfer in the mass spectrometer. An exception is umbellamine (235) (Section 13, p. 279). The occurrence of such reactions can be minimised by dispersion of the sample on glass powder before vaporisation, thus facilitating determination of the true molecular weight. The latter may be confirmed in the case of a-indolylacetic acid methyl ester derivatives by examination of reduction or demethoxycarbonylation products. 

To date, no known bisindole alkaloid has been shown to be only an artefact. In addition, no experimental evidence exists which undermines the assumption that bisindole alkaloids are actually formed from the completed monomeric partners. Support for this idea is derived from the kind of reactions apparently necessary to effect such dimerisations which are known biogenetic processes amine-aldehyde condensations, Mannich reactions, Michael additions, Friedel-Craft type condensations, Diels-Alder type processes, radical coupling etc. The observation that the skeletal distribution amongst monomeric alkaloids is reflected throughout the dimeric series lends further support. 

In an extensive study of indole alkaloids from Tabernaemontana dichotoma, Perera and co-workers reported the isolation and characterization of eight bisindole alkaloids of the vobasine-coronaridine type (90,93). Of these, the previously known alkaloids tabernamine (173), voacamine (175), and 3 R/S-hydroxyvoacamine (178) were identified from their spectral characteristics and co-TLC with authentic samples (91). UV, IR, and XH NMR data of three of the bisindole alkaloids indicated a close structural relationship to tabernamine (173), and the XH NMR of one of these alkaloids was identical to that of tabernamine, except that the signal at 6 2.62 ppm due to the N-Me group was missing. The MS and IR spectroscopic data... 

Peceyline (183), C42H48N406, mp 310°C (decomp.), [a]D -355°, and pec-eylanine (184), C44H54N4O7, mp 157-158°C, [a]D -237°, are two other vincorine-vincorine types of bisindole alkaloids isolated from Petchia cey-... 

A bisindole alkaloid isolated by the French group from Gabunia eglandulosa appears not to be voacamine, and may be new ten others, so far of unspecified structure, have been extracted from Muntafara sessilifolia, and a group of four, from Pandaca caducifolia, belong to a new structural type, but their structures have not yet been elucidated in detail. 

The third alkaloid of Capuronetta elegans, capuvosine (225), is a bisindole alkaloid of new type in which a vobasine unit is attached to one of dihydrocleavamine type. Indeed, fission of capuvosine by means of hydrochloric acid results in the formation... 

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