Vincristine from vinblastine

Vincristine may also be prepared in a semisynthetic process starting from vinblastine. Vinblastine or a salt thereof, preferably the sulfate, is oxidized with chromic acid or with one of its salts at a low temperature, the reaction mixture is neutralized or rendered alkaline and the product is separated therefrom by extraction, the extract is evaporated to dryness, the dry residue is optionally formylated, vincristine, and optionally N-demethylvinblastine also, are Isolated from the product, and the product(s) are optionally converted into their salts preferably into the sulfates, according to U.S. Patent 3,899,493. 

Vincristine and vinblastine (vinca alkaloids) comprise another class of drugs that inhibit the polymerization of microtubules but do so by binding to the tubulin molecule at a site different from the colchicine site. Cultured cells exposed to high concentrations of vinca alkaloids develop intracytoplasmic paracrystalline aggregates of tubulin. These drugs are employed clinically in cancer chemotherapy to inhibit the growth of tumors composed of rapidly dividing cells. 

Researchers from Eli Lilly pharmaceuticals, (a company founded in 1876 by Colonel Eli Lilly veteran of the US Civil War), undertook further intensive phytochemical studies and characterized 60 alkaloids, of which a group of 20 binary indole alkaloids—including vincristine and vinblastine. Vinblastine sulphate (Velbe ) inhibits the polymerization of tubulin and is used to treat generalized Hodgkin s disease and chorionepithelioma, whereas vincristine sulphate (Oncovin ) is used to treat leukemia in children. 

I 14. The answer is a. (Hardman, pp 1259, 1260.) The vinca alkaloids, vincristine and vinblastine, have proved valuable because they work on a different principle from most cancer chemotherapeutic agents They (like colchicine) inhibit mitosis in metaphase by their ability to bind to tubulin. This prevents the formation of tubules and, consequently, the orderly arrangement of chromosomes, which apparently causes cell death. 

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. 

Vincristine and vinblastine are generally considered to act specifically on the metaphase portion of the mitotic (M) stage of the cell cycle as a consequence of perturbations of the structure and function of tubulin. A characteristic action of the drugs is production of mitotic arrest in which the tJercentage of cells in mitosis in a given population of cells will rise from a few percent to 50% and more after treatment with a drug such as vinblastine. There are reports, however, that these drugs can interfere with other phases of the cell cycle in ways not clearly related to interference with tubulin function (5). 

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

Studies of the metabolism of vincristine and vinblastine have been complicated by chemical alterations of the drugs that occur during processing of samples for analysis. Extraction of these compounds under acidic conditions has been reported to minimize chemical degradation, and HPLC studies of the metabolism of vincristine indicate that microsomal preparations from mouse liver, but not those from human rhabdomyosarcoma tissue, convert vinblastine to 4-deacetyl vinblastine in vitro (38). 

Half-lives estimated after the administration of vinblastine to patients were 4 min, 1.6 hr, and 25 hr, indicating rapid distribution of the drug to most tissues, relatively rapid clearance, and a subsequent slow terminal elimination process. The distribution and initial clearance phase for vincristine are kinetically comparable to those observed for vinblastine half-lives for these phases have been reported to be 4 min and 2.3 hr in studies with vincristine. The terminal elimination phase for vincristine has been reported to be three to four times longer than that estimated for vinblastine, and the slow elimination of vincristine from susceptible neuronal tissue has been suggested to play a role in the neurotoxicity commonly observed in clinical settings with vincristine but not with vinblastine 51). 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

The vinca alkaloids comprise vincristine and vinblastine. These complex, heterocyclic alkaloids are derived from the periwinkle plant. Vindesine and vi-norelbine are semisynthetic analogues. These drugs are M-phase specitic. Binding specifically to tubulin they inhibit the polymerization of microtubules. The consequent ineffective chromosome segregation initiates apoptosis for both normal and malignant cells. 

The result of nondisjunction, loss of one chromosome, for example, may be incompatible with survival of the cell, so aneugens are often cytotoxic. This obviously only occurs in cells, which are actively dividing, therefore such compounds find use as anticancer drugs. Two examples are vincristine and vinblastine, two vinca alkaloids, derived from a plant. 

More recently, the radical cyclization onto azide groups pioneered by Kim was applied in the construction of the B/E spirocyclic junction found in the [6.5.6.5] ABCE ring system of indole alkaloids such as strychnine, the clinically used anticancer agents vincristine and vinblastine and, in particular, aspidospermine87. In model system studies, cyclization of the iodoazide 24, prepared in 6 steps, in the presence of (TMS SiH, produced the N—Si (TMS>3 protected alkaloid 25, that after washing with dilute acid afforded the amine 26 in 95% yield from 24 (equation 58). The formation of the liable N—Si(TMS)3 bond was considered to arise from the reaction of the product amine 26 with the byproduct (TMS)3SiI. 

Colchicine can arrest plant and animal cell division in vitro and in vivo. Mitosis is arrested in metaphase because of failure of spindle formation. Cells with the highest rates of division are affected earliest. High concentrations may completely prevent cells from entering mitosis, and they often die. The action also is characteristic of the vinca alkaloids (vincristine and vinblastine), podophyllotoxin, and griseofulvin. 

The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant, Vinca rosea), inhibit the polymerization of tubulin subunits into microtubuli. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Reductive cleavage (cone. HCl-SnClj-Sn) of the dimers leads to one and the same indolic base, velbanamine (173, C19H26ON2), and a different indoline, des-acetyl-vindoline (174) from vinblastine and des-JV( )-methyldesacetylvindoline (175) from vincristine. ... 

Extracts from the periwinkle are already in common use in modem medicine, for example, vincristine and vinblastine, in the treatmrait of leukemia. Egyptian studies have shown, furthermore, there is an effect on abdominal cancer too. Folklore says that Egyptian onions also are anticancer agents, and studies are under way. 

Such successes as there are against blood-related cancers can be judged intermittent, using such agents as Catharantheus and Vinca alkaloids, for example, vincristine and vinblastine, as derived from the Madagascar periwinkle Catharantheus roseus —... 

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