Alkaloids from Catharanthus roseus

The discovery of medicinal alkaloids from Catharanthus roseus G. Don (Vinca rosea L.) represents one of the most important introductions of plant products into the cancer chemotherapeutic armamentarium. The relatively unique effects and toxicities of these agents have allowed the design of multiagent chemotherapy programs that have demonstrated sufficient effectiveness to achieve cures even of advanced tumors in many instances. This great accomplishment is possible only because of the inclusion of many different drugs, including the binary Vinca alkaloids. 

Antitumor Bisindole Alkaloids from Catharanthus roseus (L.)... 

Lee H, Hong WH, Yoon JH, Song KM, Kwak SS, Liu JR. Extraction of indole alkaloids from Catharanthus roseus by using supercritical carbon dioxide. Bio-technol Tech 1992 6 127-130. 

Since the yields of active dimeric alkaloids from Catharanthus roseus is the lowest of any medicinally useful compounds (yield of VCR == 3 x 10 " %), material for studies of structure-activity relations has been scarce. Nevertheless, such studies were performed with VLB and it has been claimed that some of the products of molecular modification are more active in animal tests than VLB itself. 

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. 

A. Brossi and M. Suffness (eds.). The Alkaloids, Vol. 37 Antitumor Bisindole Alkaloids from Catharanthus roseus (L.) , vol. 37. Academic Press, San Diego, 1990. 

Renault, J.H. Nuzillard, J.-M. le Crorerour, G. Thdpenier, P. Zeches-Hanrot, M. Le Men-Olivier, L. Isolation of indole alkaloids from Catharanthus roseus by centrifugal partition chromatography in the pH-zone refining mode. J. Chromatogr. 1999, 849, 421 31. 

Bioproduction of Terpenoid Indole Alkaloids from Catharanthus roseus Cell Cultures... 

Wang Y, Lin C (2008) On the extraction method of total alkaloids from Catharanthus roseus. J Changchun Norm Univ 27 74—77... 

Verma A, Hartonen K, Riekkola M (2008) Optimisation of supercritical fluid extraction of indole alkaloids from Catharanthus roseus using experimental design methodology -comparison with other extraction techniques. Phytochem Anal 19 52-63... 

Leurosine (75) (Scheme 20) is the most abundant of the dimeric antitumor alkaloids isolated from Catharanthus roseus G. Don. Several species of Strep-tomyces produced a common metabolite of the alkaloid, and S. griseus (UI1158) was incubated with 400 mg of leurosine sulfate to obtain 28 mg of pure metabolite (180). The metabolite was identified as 76 primarily on the basis of its H-NMR spectrum. The mass spectrum indicated that the metabolite contained one oxygen atom more than 75. The H-NMR spectrum contained all of the aromatic proton signals of the vindoline portion of the molecule, and aromatic proton signals for the Iboga portion of the compound occurred as a doublet of doublets... 

The isolation of the antitumor agents vincaleukoblastine (1) and leuro-cristine (2) from Catharanthus roseus (L.) G. Don has proved to be one of the most important developments in both natural product chemistry and the clinical treatment of cancer during the 1960s to 1980s. More alkaloids (over 90) have been isolated from C. roseus than from any other plant, and because of the complexity of the alkaloid mixture this work has required the most advanced isolation and structure determination techniques. The exceptional interest in the broad spectrum of antitumor activity of these compounds has resulted in numerous achievements in the pharmaceutical, clinical pharmacologic, and therapeutical sciences. Simultaneously, strenuous efforts have been made in three areas of the natural product chemistry (i) elaboration of a practical semisynthesis of... 

Alkaloids with Unknown Structures Isolated FROM Catharanthus roseus... 

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... 

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. 

Pasquali, G., Goddijn, O. J. M., de Waal, A., Verpoorte, R., Schilperoort, R. A., Hoge, J. H. C. and Memelink, J. 1992. Coordinated regulation of two indole alkaloid biosynthetic genes from Catharanthus roseus by auxin and elicitors. Plant Molecular Biology, 18 1121-1131. 

Geerlings A, Martinez-Lozano Ibanez M, Memelink J, van der Heijden R, Verpoorte R (2000) The strictosidine 6-D-glucosidase gene from Catharanthus roseus is regulated coordinately with other terpenoid-indole alkaloid biosynthetic genes and the encoded enzyme is located in the endoplasmic reticulum. J Biol Chem 275 3051-3056... 

The rauwolfia alkaloids are now hardly ever prescribed in the UK, either as antihypertensives or as tranquillizers. Over a period of a few years, they have been rapidly superseded by synthetic alternatives. Reserpine has also been suggested to play a role in the promotion of breast cancers. Both ajmalicine (= raubasine) (Figure 6.76) and ajmaline (Figure 6.82) are used clinically in Europe, though not in the UK. Ajmalicine is employed as an antihypertensive, whilst ajmaline is of value in the treatment of cardiac arrhythmias. Ajmalicine is also extracted commercially from Catharanthus roseus (see page 357). 

Cathenamine (100) has been identified as an early intermediate in terpenoid indole alkaloid biosynthesis (cf. Vol. 8, p. 27). It has also been isolated from Guettarda eximia. Another alkaloid, 4,21-dehydrogeissoschizine (99), has now been isolated from this plant it is readily converted into (100) in alkaline solution.29 On incubation with an enzyme preparation from Catharanthus roseus cell cultures in the presence of NADPH at pH 7, (99) was converted into ajmalicine (102), 19-ep/-ajmalicine (103), and tetrahydroalstonine (104), which are the normal products with this enzyme preparation. In the absence of NADPH, cathenamine (100) accumulated.30 The reaction to give (100) proceeded linearly with time, and was dependent on the concentration of protein and substrate. No conversion occurred in the absence of enzyme. 

Within the natural products field, the investigation of complete biosynthetic pathways at the enzyme level has been especially successful for plant alkaloids of the monoterpenoid indole alkaloid family generated from the monoterpene gluco-side secologanin and decarboxylation product of tryptophan, tryptamine [3-5]. The most comprehensive enzymatic data are now available for the alkaloids ajmalicine (raubasine) from Catharanthus roseus, and for ajmaline from Indian Rauvolfia serpentina [6] the latter alkaloid with a six-membered ring system bearing nine chiral carbon atoms. Entymatic data exsist also for vindoline, the vincaleucoblastin (VLB) precursor for which some studies on enzymatic coupling of vindoline and catharanthine exist in order to get the so-called dimeric Catharanthus indole-alkaloids VLB or vincristine [7-9] with pronounced anti-cancer activity [10, 11]. 

Fig. 1 First example of a complete biosynthetic pathway to an alkaloid (ajmalicine = raubasine) based on enzymatic reactions elucidated by isolation of the single enzymes from Catharanthus roseus cell suspension cultures...

DE LUCA, V., BALSEVICH, J., TYLER, R.T., KURZ, W.G.W, Characterization of a novel V-methyltransferase (NMT) from Catharanthus roseus plants. Detection of NMT and other enzymes of the indole alkaloid biosynthetic pathway in different cell suspension culture systems. Plant Cell Rep., 1987,6,458-461. 

Extensive studies to quantitate the production of indole alkaloids in Catharanthus roseus hairy root cultures have revealed that they accumulate several compounds including ajmalicine, serpentine, catharanthine, tabersonine, horhammericine, and lochnericine.27, 28 The presence of tabersonine in hairy roots has raised speculations that this intermediate in vindoline biosynthesis, together with catharanthine, is transported from this potential site of biosynthesis through the vasculature to the stem and to the leaves where tabersonine is further elaborated into vindoline within laticifers and/or idioblasts.26 However, oxidized derivatives of tabersonine, such as horhammericine and lochnericine, are present at 5 to 15 times the levels of tabersonine in hairy roots,27 and presumably this prevents their transport and/or use for vindoline biosynthesis. In this context, it would be interesting to... 

Quaternary ammonium compounds are important as osmoprotectants in times of water deficiency and cold stress, as well as being constituents of membrane phospholipids, p-Alanine and phosphoethanolamine are each methylated three times on their nitrogens to produce the products P-alanine betaine and phosphocholine, respectively (Fig. ll.l).24"27 An example of O-methylation and N-methylation occurring on the same molecule can be found in the indole alkaloid vindoline from Catharanthus roseus (Fig. 11.1) 28,29... 

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. 

The antitumor alkaloids vinblastine (1) and vincristine (2) were the first natural products to be used on a large scale as anticancer agents, and they thus blazed the trail for others that came afterward. Vinblastine (as vincaleukoblastine) was isolated from Catharanthus roseus (L.) G. Don, which was formerly known... 

The Vinca alkaloids, vinblastine (64) and vincristine (65), isolated from Catharanthus roseus, have contributed significantly to the understanding and treatment of cancer (56, 57). These... 

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. 

Terpenoid Indole Alkaloids.—Crude preparations from Catharanthus roseus seedlings and from tissue cultures have been shown to be capable of synthesizing in good yield from tryptamine (110) and secologanin (111) with added co-factors, geisso-schizine (112) and ajmalicine (113), representatives of the first major class of terpenoid indole alkaloids (Corynanthe). Geissoschizine was metabolized to ajmalicine and several other unidentified alkaloids (for reviews of biosynthesis in intact plants see ref. 106). The catabolic turnover of vindoline and catharanthine in C. roseus has been studied. ... 

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