Catharanthus roseus alkaloids

Oudin A, Courtois M, Rideau M, Clastre M. The Iridoid Pathway in Catharanthus roseus Alkaloid Biosynthesis. Phytochemical Reviews 2007 6 259-276. 

ST-PIERRE, B., VAZQUEZ-FLOTA, F.A., DE LUCA, V., Multicellular compartmentation of Catharanthus roseus alkaloid biosynthesis predicts intercellular translocation of a pathway intermediate. Plant Cell, 1999, 11, 887-900. 

Mujib A, llah A, Aslam J, Fatima S, Siddiqui ZH, Maqsood M. Catharanthus roseus alkaloids application of biotechnology for improving yield. Plant Growth Regul 2012 68(2) lll-27. 

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. 

Iridoids and their related alkaloids are widely spread in angiosperms and are found in 13 orders and 70 families including Rutales, Buxales, Hamamelidales, Comales, Loasales, Gentianales, etc. Important iridoids are loganin, found in high amounts in Strychnos nux-vomica and in Catharanthus roseus, and secologanin found especially in Caprifoliaceae. 

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... 

Recently, Cordell and collaborators (51) reported the discovery of (—)-16-epi-(Z)-isositsirikine (48) from the leaves of Catharanthus roseus (L.) G.Don and Rhazya stricta Decaisne, the first isositsirikine-type alkaloid with Z geometry in the C-20 ethylidene side chain. Moreover, they gave reliable structure assignments for (-)-( )-isositsirikine (46) and (—)-16-epi-( )-isositsirkine (47). 

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... 

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. 

Rniz-May E, Galaz-Avalos RM, Loyola-Vargas VM. (2009) Differential secretion and accumulation of terpene indole alkaloids in hairy roots of Catharanthus roseus treated with methyl jasmonate. Mol Biotechnol 41 278-285. 

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 enzyme responsible for the stereospecific condensation of trypt-amine and secologanin 34) was called strictosidine synthase, and its presence was demonstrated by Treimer and Zenk 194) in a number of indole alkaloid-producing plants, including Amsonia salicifolia, Catharanthus roseus, Ochrosia elliptica, Rauwolfia vomitoria, Rhazya orientalis, Stem-madenia tomentosa. Vinca minor, and Voacanga africana. Enzyme activity as high as 1698 pkat/mg protein was observed for O. elliptica. No... 

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. 

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

VLB and VCR are said to be present in only minute amounts in Catharanthus roseus (L.) G. Don 0.00025% of leaf dry weight), and their separation from other monomeric or binary alkaloids involves a complicated and tedious procedure based on their differential basicity followed by chromatography. Industrial production of VLB and VCR has therefore been a serious problem, and consequently these drugs are among the most expensive on the pharmaceutical market. 

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 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.)... 

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. 

McCoy E, O Connor SE, Directed biosynthesis of alkaloid analogs in the medicinal plant Catharanthus roseus, J Am Chem Soc 128 14276-14277, 2006. 

Catharanthus roseus, biosynthesis of terpenoid indole alkaloids in, 49, 222 (1997) Celastraceae alkaloids, 16, 215 (1977)... 

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. 

Figure 74. Chemical model of indole alkaloid formation in Catharanthus roseus. The arrows represent the direction of formation, the flnx of compounds skeleton construction.

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