Catharanthus alkaloids Vincristine

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 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). 

Catharanthus roseus (Apocynaceae) Alkaloids vincristine, ajmalicine, lochnerine, serpentine and tetrahydroalstonine, vinblastine. Vincristine, vinblastine (GC) (59)... 

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. 

Two clinically useful bisindole alkaloids, vincristine (55) and vinblastine (56), are among the most expensive of all plant-derived drugs (as much as 23,000 per gram), because of their low abundance in the source plant Catharanthus roseus (formerly placed in the Vinca by some workers) and... 

Indole Indole alkaloids, Catharanthus roseus Vincristine, vinblastine, vindesine Anticancer, cytostatic... 

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. 

Vincristine (VC) and vinblastine (VB) are dimeric catharanthus alkaloids isolated from the plant Catharanthus roseus. A capillary zone electrophoresis (CZE) was conducted for systematic and comprehensive study of the separation and quantification of two dimeric catharanthus alkaloids. Various separation parameters such as buffer concentration and pH, column internal diameter, and applied voltage were studied column, 72 cm (57 cm effective length) x 75 pm I.D. buffer, 0.2 M ammonium acetate solution, pH 6.2 and an applied voltage of 10 kV. Although the separation of VB and VC was the primary focus, the separation parameters determined in this study can be applied to the separation of other alkaloids as well. Separation of other alkaloids in the plant samples was observed under conditions presented in this work. A secondary objective of this study was to develop a method with experimental conditions which could be applied to electrophoresis-mass spectrometry. For this purpose, ammonium acetate buffers, which are more compatible with mass spectrometry than the widely used phosphate buffers, were used exclusively. Also, methanol-water-acetic acid was used as external buffer for the same reason [16]. 

Where to chemical syntiiesis is not viaUe then the active imnciple must be obtained either completely or partially from a natural source. Often, however, active principles are present only in minute amounts in material fmn the source plant. The classical example of this situation refers to the anti-leukaemic dimeric alkaloids vincristine and vinblastine from Catharanthus roseus. These compounds may be obtained from the leaves of periwinkle plants grown in the field, but the yield of active principle is less than 0.001% (w/w) making these amongst die most expensive of drugs. Similariy, die content of artemisinin in A. annua has been shown to be rather low and variaUe widiin die range 0.003 -0.21% w/w (8). 

Until separation techniques such as chromatography (28,29) and counter-current extraction had advanced sufficientiy to be of widespread use, the principal alkaloids were isolated from plant extracts and the minor constituents were either discarded or remained uninvestigated. With the advent of, first, column, then preparative thin layer, and now high pressure Hquid chromatography, even very low concentrations of materials of physiological significance can be obtained in commercial quantities. The alkaloid leurocristine (vincristine, 22, R = CHO), one of the more than 90 alkaloids found in Catharanthus roseus G. Don, from which it is isolated and then used in chemotherapy, occurs in concentrations of about 2 mg/100 kg of plant material. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

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. 

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... 

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... 

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

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. 

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... 

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle Catharanthus roseus). The vindoline synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin s disease (a form of lymphoid cancer), while vincristine is used clinically in the treatment of children s leukaemia. Vincristine is more neurotoxic than vinblastine. 

A major problem associated with the clinical use of vinblastine and vincristine is that only very small amounts of these desirable alkaloids are present in the plant. Although the total alkaloid content of the leaf can reach 1 % or more, over 500 kg of catharanthus is needed to yield 1 g of vincristine. This yield (0.0002%) is the lowest of any medicinally important alkaloid isolated on a commercial basis. Extraction is both costly and tedious, requiring large quantities... 

The observation that fractions of the rosey periwinkle, Catharanthus rosea, produced severe leukopenia, resulted in the isolation and development of two major anticancer drugs, vincristine and vinblastine. These two complex, dimeric indole-indoline alkaloids are important in the treatment of acute childhood leukemia (vincristine), Hodgkin s disease (vinblastine), and metastatic testicular tumors (vinblastine), and continue to be manufactured today by mass cultivation and processing of their natural source. 

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... 

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]. 

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. 

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