Bisindole alkaloids of Catharanthus

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

Scheme 8. Current biogenetic ideas for the bisindole alkaloids of Catharanthus roseus.

The bisindole alkaloids of Catharanthus exhibit ambiphilic behavior in solution, owing, in large part, to their gross lipophilic character combined with the presence of four nitrogen atoms of varying basicity. The upper... 

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. 

Bisindole alkaloids of Catharanthus C-20 position as a functional hot spot in, 37, 133 (1990) isolation, structure elucidation and biosynthesis, 37,1 (1990) medicinal chemistry of, 37,145 (1990)... 

MEDICINAL CHEMISTRY OF BISINDOLE ALKALOIDS FROM CATHARANTHUS... 

The 4-acyl derivatives of 4-deacetylvinblastine (98) are among the earliest semi-synthetic compounds prepared in exploring the medicinal chemistry of the bisindole alkaloids from Catharanthus. By 1965, the clinical utility of vinblastine (1) and vincristine (2) was firmly established, and the naturally occurring congeners leurosine (3) and leurosidine (4) had been well characterized with respect to their experimental antitumor activity. Since these compounds were substantially less active in animal tumor... 

Vindolicine (vindoline 10,10 -dimer) and fourteen bisindole alkaloids of the vinblastine group have been isolated from the aerial parts of Catharanthus ovalis.ny These include leurosine, 21 -hydroxyleurosine, vinblastine, 20 -deoxy-leurosidine, 20 -deoxyvinblastine, pleurosine, Catharine, catharinine, vincristine, and vincathicine. A new alkaloid is 21 -oxoleurosine (198), which has also been found recently in Catharanthus roseus.U8 The three remaining alkaloids are vincovaline (199) and vincovalinine (16 -desmethoxycarbonyl-leurosine), whose structures119 have now been confirmed, and vincovalicine, which has... 

McCormack, J. J., Pharmacology of antitumor bisindole alkaloids from Catharanthus, in The Alkaloids, Vol. 37 (A. Brossi and M. Suffness, eds.), 205-228, Academic Press, New York, 1990. 

McCormack, J.J. (1990) Pharmacology of Anti-tumor Bisindole Alkaloids from Catharanthus, Vol. 37. Academic Press, Inc., Orlando, FL, pp. 205-226. 

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. 

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. 

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... 

Higher plants are a very important source of medicinally useful compounds. Catharanthus roseus is one of the most important of these plants, and this chapter focuses on the further isolation work directed at the identification of new potentially more active and/or less toxic bisindole alkaloids. In addition, the biosynthesis of the indole alkaloids of C. roseus is reviewed. While the former area of research has been dominated by sophisticated high-field NMR and high-resolution mass spectral analyses. 

The chemical reactivity of N-6 (or N ), directed entirely by the basicity of this atom, is controlled by the nature and stereochemistry of the substituents at C-4 (vide supra). Oxidation of N-6 occurs under mild conditions in several naturally occurring bisindole alkaloids. Thus, treatment of a dichloromethane solution of leurosine (4) with m-chloroperben-zoic acid at -20°C for 4 hr gives the N -oxide (15) in greater than 90% yield after preparative reversed-phase chromatography (46). Leurosine A/ -oxide has also been isolated from Catharanthus roseus and should therefore be considered a naturally occurring bisindole (50). The analogous conversion of vinblastine (1) to its A/ -oxide (16) proceeds under similar conditions but requires longer exposure to the peraeid (24 hr) (5/) 3, 4 -anhydrovinblastine is converted to its N -oxide (17) in 10 min at 0°C... 

The functionality associated with N-1 of the vindoline portion of the bisindole alkaloids confers much biological diversity to these compounds. This property is exemplified by the differences in the cellular pharmacology, antitumor efficacy, and toxicity of vinblastine (1) and vincristine (2). Since 1 is isolated from extracts of Catharanthus in approximately 10-fold greater yield, it is not surprising that several oxidative methods have... 

Vinblastine (4) and vincristine (5) are closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus roseus (L.) G. Don (formerly known as Vinca rosea L.), the Madagascar periwinkle. Both of these anticancer agents, known as vinca alkaloids in the medical literature, are specific binders of tubulin, leading to tubulin depolymerization and cell cycle arrest in the metaphase stage. 

Another group of alkaloids with antimitotic properties are the bisindole alkaloids, such as vinblastine and vincristine, which have been isolated from Catharanthus roseus (Apocynaceae). These alkaloids also bind to tubulin (312). Both alkaloids are very toxic, but are nevertheless important drugs for the treatment of some leukemias. 

In 1959 a series of bisindole alkaloids were isolated from Vinca rosea L. Catharanthus roseus G. Don). Of signal importance have been vinblastine (169) (= vincaleukoblastine) and vincristine (170) (= leurocristine), both of which show anti-tumour activity (see Section 18, p. 333). Structurally clarified also are leurosidine (= vinrosidine), leurosine, pleurosine, and isoleurosine , while only one half of Catharine is known. 

Tissue or cell cultures of Catharanthus roseus continue to be investigated, in the search for improved methods of production of pharmacologically important alkaloids. Three such investigations have recently been reported, and although several alkaloids were obtained, including some heteroyohimbine and yohimbine alkaloids, no new ones were encountered, and none of the valuable bisindole alkaloids was obtained. However, pleiocarpamine, one of the alkaloids isolated, had not previously been 6 2... 

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