Vincristine from Catharanthus roseus

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. 

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. 

Yang X et al.. Preliminary study of a vincristine-producing endophytic fungus isolated from leaves of Catharanthus roseus, Zhongcaoyao 35 79—81, 2004. 

Other examples of natural drugs may be pointed out streptozotocin (from streptomyces achromogenes), bleomycin (from streptomyces verticillus), adriamy-cin and daunomycin (from streptomyces pencetius), mitomycin C (from streptomyces caesipitosus), vincristine, vinblastine and vindoline (from catharanthus roseus or vinca rosea L.). 

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. 

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. 

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. 

This reaction has been extensively studied in the case of the chlopromazine radical (R -mediated aminopyrine (S) oxidation [41], a typical reaction for xenobiotics, as well as in the case of the vindoline radical (R -mediated catharanthine (S) oxidation [42], a key reaction in the biosynthesis of the anticancer drugs, vinblastine and vincristine, which are obtained from Catharanthus roseus. 

Vincristine is the nonproprietary name for the alkaloid originally called leurocris-tine. It is obtained from the plant Vinca rosea Linn. (Catharanthus roseus G. Don) of the family Apocynaceae(Madagascar periwinkle). Vincristine sulfate is the 1 1 sulfate salt of vincristine. The structure of vincristine differs from that of vinblastine- only by the substituent at the anilino-nitrogen in the vindoline portion of the molecule. Thus it is des-Na-methyl-Na-formyl vinblastine. It is also known by the code numbers NSC-67571 and 372313 and is abbreviated to VCR and VCR sulfate. Elucidation of the molecular structure, stereochemistry, and absolute configuration of this compound is found in the literature ... 

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. 

So far about 72 alkaloids have been isolated from Vinca rosea Liim, genus Catharanthus roseus (Family Apocynaceae). Out of these 24 dimeric alkaloids only six possess antineoplastic activity but specifically two i.e., vincristine, vinblastine, are used clinically in human neoplasms. These are cell-cycle specific agents. 

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. 

Initial methods for the isolation of vinblastine from the periwinkle plants (vinca rosea) had been described (5,7,23-25) and well documented in several texts including the previous profile of vinblastine sulfate (12). Isolation of vinblastine and vincristine from Catharanthus roseus continues to receive attention, and several procedures have been reported (mainly in the patent literature) for the isolation and separation of these alkaloids (24-29). Extracts of Catharanthus roseus have been found to contain N-demethylvinblastine and this can be used to prepare vincristine by formylating the alkaloid mixture before separation and purification (30). 

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