Catharanthus alkaloids Vinblastine

The two alkaloids vinblastine and vincristine found in Catharanthus roseus have been recent targets of total synthesis because of their potency in cancer chemotherapy. The reduced tree diagram for the Fukuyama plan to vincristine is shown in Figure 4.66. There are three points of convergence, four branches leading to the target product and four tiers of reaction yields. 

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... 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Treatment of cells with vinblastine or vincristine can result in the formation of paracrystals, complexes containing the alkaloid molecules and tubulin dimers in a 1 1 ratio. Paracrystal formation in neuronal tissue of a freshwater snail has been proposed as a model for the neurotoxic effects of Catharanthus alkaloids and derivatives 44). Vincristine is approximately 10-fold more active than vinblastine as an inducer of paracrystal formation when snail neuronal tissue is treated with high concentrations (150 lM) of the alkaloids. 

Catharanthus (yincd) alkaloids [Vinblastine (4), Vincristine (5)] Catharanthus roseus (L.) G. Don (Madagascar periwinkle) Anticancer... 

The Catharanthus (Vincd) alkaloids, vinblastine (4) and vincristine (5), are not only very useful anticancer agents, but are also bona fide lead compounds. A semisynthetic vinblastine (4) analogue, vinorelbine (52) is indicated for lung and mammary carcinomas. Vinflunine was further developed from vinorelbine, and has shown promise in phase II clinical trials. >93... 

A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12. They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea (= Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the Aa-formyl analog, CIV, forms part of the dimeric alkaloid leurocristine (5, 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V. rosea and its dihydro-decarbomethoxy derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpa species (53). ( + )-Vincadif-formine (XCIII, 6, 74) has already been mentioned as the racemic form of (— )-6,7-dihydrotabersonine (Section II, O). It has been found in V. difformis and in Rhazya stricta (51b) where the (+) form also occurs. 

Periwinkle, Catharanthus (Vinca) roseus contains the pharmacologically important indole alkaloids vinblastine and vincristine, which are now available commercially. Vinblastine sulfate and vincristine sulfate are used for the treatment of generalized Hodgkin s disease and chorionepithelioma and for the treatment of leukemia in children 45). 

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... 

Catharanthus alkaloids, particularly vinblastine (Al) and vincristine (A2), are well known anticancer drugs, which are used clinically to treat Hodgkin s lymphoma and acute childhood lymphoblastic leukemia, respectively. These alkaloids interact with tubulin, a protein necessary for cell division, and are inhibitors of mitosis (the process of cell division). 

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... 

Barnett CJ, Cullinan GJ, Gerzon K, Hoying RC, Jones WE, Newlon WM, Poore GA, Robison RL, Sweeney MJ, et al. Structure-activity relationships of dimeric Catharanthus alkaloids. 1. Deacetyl vinblastine amide vindesine sulfate. J. Med. Chem. 1978 21 88-96. 

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. 

Higher plants have evolved an extraordinary variety of secondary metabolic pathways, the resulting products of which have been put to use by man providing pharmaceuticals for drug use, insecticides and various allelochemicals for pest control, and extracts for the flavor and fragrances industries. In spite of advances in synthetic organic chemistry, plants remain a major source of natural products, particularly in the specialty chemicals industry. Compounds, such as the insecticide derived from Azadiraohta indioa or the antitumor alkaloids vinblastine and vincristine found in periwinkle (Catharanthus roseus) (1 ), have complicated structures which preclude at the present time the development of an economical chemical synthesis (Figure 1). In the case of... 

Several important alkaloids have been isolated from Catharanthus roseus plants ajmalicine (34) and serpentine (35) from the root, and the dimeric alkaloids vinblastine (36) and vincristine (37) from the leaves. Therefore, much research has been done on production of these alkaloids by means of plant cell culture. Catharanthus roseus is, in fact, one of the most widely studied plants for the production of secondary metabolites in cell culture systems. We here discuss the two types of alkaloids separately. Table XXIX summarizes patents concerning the production of alkaloids by means of cell cultures of C. roseus. 

The therapeutic and economic importance of the alkaloids vinblastine (36) and vincristine (37) has stimulated a major research effort on the plant cell biotechnology of Catharanthus roseus. This work, which has recently been extensively reviewed (592), has resulted in several patents (Table XXIX). Concomitantly, modern analytical procedures, for example, HPLC 635,637), GC-MS 636), immunoassays 638-641), and supercritical fluid chromatography/mass spectrometry 642), have been developed to high sensitivity and selectivity to study alkaloid formation in plant tissues. 

Two dimensional TLC technique was reported for the separation of more complex mixture of catharanthus alkaloids (113) The BP (6) adopted a TLC technique to test for the presence of related alkaloids in vinblastine sulfate sample (checking the purity of the sample) ... 

This system is employed for the analysis of Catharanthus alkaloids including vinblastine C118). 

The following reversed-phase system has been used for the analysis of Catharanthus alkaloids including vinblastine by thermospray liquid chromatography-mass spectrometry (120). u Bondapak Ci8 (30cm x 3.9mm), reversed-phase column. 

This reversed-phase system is described for the determination of vinblastine and other Catharanthus alkaloids. The relative standard deviation, the limit of detection and the recovery were 1.63-3.52%, 10 yg/ml and 96.6-102% respectively (122). 

Considerable attention continues to.be focussed on the vinblastine group of alkaloids, both in connection with the synthesis of the alkaloids themselves and structural variants that might prove to have useful pharmacological properties. Vinblastine itself is one of the alkaloids produced in the callus tissue culture of Catharanthus roseus. H.p.l.c. is recommended for the separation of mixtures of Catharanthus alkaloids retention times of the alkaloids differ markedly, and result in good separations of both monomeric and dimeric alkaloids. 

Occasionally, the bisindole alkaloids vinblastine (vincaleukoblastine, VLB) and vincristine (leurocristine,VCR) are referred to as Vinca alkaloids, which is a misnomer these bisindole alkaloids should be correctly referred to as Catharanthus alkaloids. 

Several anticancer drugs are indoles, the most famous of which are the Catharanthus roseus plant alkaloids vinblastine (124) and vincristine (125) (Scheme 18), both of which continue to be important drugs for the treatment of Hodgkin s disease, childhood leukemia, and other cancers [141-143], The rebeccamycin analogue NSC-655649 (126) is in phase n trials for the treatment of metastatic renal cell cancer... 

Vinca alkaloids, Catharanthus alkaloids a group of about 60 iridoid indole alkaloids from Vinca (Catharanthus) spp. Structurally, they are tetra- or penta-cyclic indole derivatives with an iridoid component, e g. vindoline, [a]n -18° (CHCI3), m.p. 174-176°C, and vincamine, [ci]d + 41° (pyridine), m.p. 232-233 °C. These are accompanied in the leaves by small quantities (about 0.005%) of two dimeric V.a., i.e. Vinblastine (see) and fincristine (see) (Hg.). Tryptophan and mevalonic acid are biosynthetic precursors... 

Genomic and transcriptomic technologies have been used to rapidly identify biosynthetic steps. There are currently over 40,000 expressed enzyme tags (ESTs) generated fi om alkaloid-producing plants that have been used to isolate genes involved in the alkaloid pathway [7]. Some alkaloid biosynthetic steps occur as spontaneous chemical reactions without the use of enzymes, for example, conversion of the intermediate neopine into codeinone in the morphine biosynthetic pathway. Also, some enzymes may catalyze two or more separate reactions in the pathway, for example, hyoscyamine 6-hydroxylase, which carries out two consecutive steps in the scopolamine biosynthetic pathway. Alkaloid biosynthesis also involves compartmentalization. Tissue-specific localization studies have shown that sequential biosynthetic enzymes can occur in distinct cell types [8, 9]. During the biosynthesis of the indole alkaloids vinblastine and vincristine in Catharanthus roseus, different enzymatic steps are carried out in different cellular compartments (Fig. 8.5) [10]. Various steps in the pathway are carried out in different types of cell. This requires the intercellular transport of metabolic intermediates. Similarly, scopolamine biosynthesis also involves two different cell types. 

L-Tryptophan is an indole ring containing aromatic amino acid derived via the shikimate pathway. The tryptophan-derived alkaloids are found in eight families, of which, Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae are the best sources. The alkaloids under discussion are the Catharanthus alkaloids, namely, ajmalicine, tabersonine, catharanthine, vindoline, vinblastine, vincristine and vincamine as well as terpenoid alkaloids derived from other families, namely, yohimbine, reserpine, strychnine, brucine, and ellipticine. The above-mentioned alkaloids are pharmacologically very important and hence extremely valuable. This chapter describes various aspects of the tryptophan-derived alkaloids like occurrence, biological activity, phytochemistry, and commercial and biotechnological aspects. 

When LEE is used, it is advisable to do either very quickly or from only a moderately alkaline aqueous solution, which was basified by sodium carbonate or ammonia. The Catharanthus alkaloids was prepared by LEE from the 75 % ethanol extract at pH 3.5, then adjusted the basic to pH 12 and finally extracted by chloroform [7]. Three major alkaloids, vinblastine and its monomeric precursors (vindoline and catharanthine), were monitored in transformed root cultures of Catharanthus roseus, after rapid sample preparation by LEE in our previous work [8]. The extraction method was the same as above. Other Catharanthus alkaloids, such as vindoline, catharanthine, and anhydrovinblastine, were prepared by LEE from the methanol extraction [9]. 

In a previous work, we developed a LC-UV method for simultaneous determination of five active alkaloids vinblastine, vindoline, ajmalicine, catharanthine, and vinleurosine in Catharanthus roseus. HPLC analyses were performed on an 1100 HPLC instrument equipped with a binary pump, a UV detector, an autosampler, and... 

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