Vinblastine vindoline

Catharanthus roseus Ajmalicine Catharan thine Vindoline Vinblastine Vincristine Vindesine Alioline... 

Figure 42. Diagram of the vindoline, vinblastine and vincristine pathway.

Synthetic methodology and total syntheses of nitrogen-containing natural products, such as the antibiotic 593A, /1-lactams, indole alkaloid vincadifformine, po-rothramycin B, vindolin, vinblastin 03YGK620. 

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. 

Vinblastine and vincristine are synthesized from monomers catharanthine and vindoline. Vinblastine and vincristine differ in the nature of the substituent group on the dihydroindole moiety, which is either a methyl group (vinblastine) or a formyl group (vincristine) [20]. 

Aspect Condition/Treatment Culture type Ajmalicine Tabersonine Catharanthine Vindoline Vinblastine Vincristine References... 

Tables 4.32 and 4.33 summarize the metrics for the synthesis plans for both products. The Fukuyama plans to both targets are very similar differing only in the very late stages of each plan. The Kuehne plan to vinblastine is considerably shorter than the Fukuyama one since it uses (—) -vindoline as an available starting material in stage 11. This explains why its overall kernel RME is 17 times larger than that of the Fukuyama plan. For a more fair comparison, if the upper two branches leading to (—)-vindoline are omitted from the Fukuyama plan, the number of stages remain the same at 27 but the number of reactions and inputs decreases to 29 and 47, respectively. These changes result in an increase in overall kernel RME from 0.3% to 0.5% but it is still an order of magnitude less than that determined for the Kuehne...

A total synthesis of (+ )-vinblastine widely used in cancer chemotherapy, has been reported. It includes the synthesis of (-)-vindoline. 1,3-Dipolar cycloaddition of a nitrile oxide has played an important role in the preparation of the indoloazacycloundecane moiety, whose coupling with (-)-vindoline occurs with the desired stereochemistry, leading to an intermediate readily transformed to the target (+ )-vinblastine (492). 

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. 

Scheme 14. The structures of vindoline (46) and derivatives, vinblastine and vincristine (52 and 53), and dihydrovindoline ether (54).

The vinblastine alkaloids are important chemotherapeutic materials, and are well known for their antitumor properties. A two-electron oxidation of alkaloid cantha-ranthine (125) followed by nucleophilic capture of the resulting imminium ion (126) by Cio of vindoline (127), afforded (128) and provided access to this important class of materials (Scheme 29) [56]. 

Examination of the C-NMR spectra of roseadine (23) (Table XI) through comparison with vindoline (3) and leurosine (11) permitted the assignment of all carbons of the dihydroindole unit. The carbons of the indole nucleus were assigned by comparison with vinblastine (1), and the presence of three deshielded carbons, a methine carbon at 8 142.9 and two quaternary carbons at 8 133.2 and 169.2, were observed. The latter was assigned to the methoxycarbonyl carbon, which is shielded somewhat from its characteristic chemical shift of 8 174 1 ppm in the vinblastine series by attachment of an olefinic unit. The other two deshielded carbons at 8 133.2 and 142.9 could be assigned as C-18 and C-17, respec-... 

Goodbody and co-workers (7/9) have examined the production of alkaloids in root and shoot cultures induced from seedlings of C. roseus. The pattern of alkaloids in the root cultures was similar to that of the roots from intact plants. Thus ajmalicine (39) and catharanthine (4) were produced, but no vindoline (3), a major leaf alkaloid, and no bisindole alkaloids. Similarly, the pattern of the alkaloid content of the shoot cultures was like that of the leaves of the intact plant, showing the presence of vindoline (3), catharanthine (4), and ajmalicine (39), with 3 predominating. A search for the bisindole alkaloids in the cultures indicated the presence of anhydrovinblastine (8) and leurosine (11) in the shoot cultures (2.6 and 0.3 xg/g fresh weight, respectively), but no vinblastine (1) or vincristine (2). 

Continued work by the same group 123) has led to the first isolation of vinblastine (1) from a multiple shoot culture of C. roseus. The most productive line, MSC-B-1, consisted of two distinctly different tissues, multiple shoots and unorganized tissue, and was maintained growing and productive for 30 months. Vinblastine (1) was isolated by HPLC, and the content was estimated to be 15 jjig/g dry weight. Production of this alkaloid was greater than that in the callus culture but less than that observed for the parent plant, even though the levels of catharanthine (4) and vindoline (3) were about the same. 

The enzyme-catalyzed formation of anhydrovinblastine (8) from catharanthine (4) and vindoline (3) was first examined by Kutney and co-workers (170,219) using a cell-free preparation. [ao f- H]Catharanthine (4) and [acety/- C]vindoline (3) were incubated for 3-8 hr, both separately and jointly with a preparation from C. roseus, which led to the isolation of labeled anhydrovinblastine (8) and leurosine (11) incorporations were of the order of 0.54 and 0.36%, respectively. On this basis, anhydrovinblastine (8) was proposed as the key biosynthetic intermediate en route to vinblastine (1) and vincristine (2). 

The conversion of anhydrovinblastine (8) to vinblastine (1) has been examined by several different groups, using intact plants, cell suspension systems, and cell-free preparations. From the studies discussed above it was clear that 3, 4 -anhydrovinblastine (8) was probably the initially formed intermediate in the condensation of vindoline (3) and catharanthine (4) prior to vinblastine (1). Kutney and co-workers have reported (225,226) on the biotransformation of 3, 4 -anhydrovinblastine (8) using cell suspension cultures of the 916 cell line from C. roseus a line which did not produce the normal spectrum of indole alkaloids. After 24 hr the major alkaloid products were leurosine (11) and Catharine (10) in 31 and 9% yields, respectively, with about 40% of the starting alkaloid consumed. 

The real breakthrough toward synthesis of vinblastine and, in fact, the first significant laboratory preparation of binary indole-indoline alkaloids with the natural C-16 -C14 PARF configuration, was due to the work of the Potier-Langlois team at Gif (38,39 for reviews, see Refs. 40 and 41), buttressed by results obtained by the Kutney group in Vancouver (42,43,44), and the efforts of Atta-ur-Rahman and associates in Karachi. Their basic idea, which relied on the biogenetic consideration that binary indole-indoline alkaloids are formed in plants by the union of vindoline... 

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