Vinblastine from Vinca rosea

Svoboda first obtained vincristine by rechromatography of the post-vinblastine eluates collected during the isolation of vinblastine from Vinca rosea (also see Vinblastine Sulfate profile, this publication) and subse-... 

Vincristine, leurocrisliae a dimeric indole alkaloid closely related to vinblastine, from Vinca rosea (see Vinca alkaloids). It is used mainly for the treatment of acute leukemia in children, and against various other neoplasmic growths. 

NSC 49842 Velban Velbe ) is one of the vinca alkaloids from Vinca rosea (Catharanthus roseus) (Apocynaceae). It is a cytotoxic ANTICANCER AGENT used by injection for acute leukaemias, lymphomas and some solid tumours, vinblastine sulfate vinblastine, vincaleucoblastine vinblastine, vincaleukoblastine vinblastine. 

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. 

Leurosidine (181).— The third bisindole alkaloid of this group from Vinca rosea L. to be investigated was leurosidine (181), C46H58O9N4 (= vinrosidine), an isomer of vinblastine (169). 

Vinblastine is an alkaloid derived from Vinca rosea, the periwinkle plant. Its mechanism of action involves depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle. The drug binds specifically to the microtubular protein tubulin in dimeric form the drug-tubulin complex joins to the forming end of... 

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. 

The antibiotic griseoviridin (60) has been mentioned (see Section 9.27.3.3). The antitumor alkaloid vinblastine (411) (from Vinca rosea) is used widely in the treatment of Hodgkin s disease <89CC518>. The dibenz[(//]azonine alkaloids neodihydrothebaine (412 R = OMe, = H) and bractazonine (412 R = H, R = OMe) have been isolated from Papaver bracteatum <84H(22)2007> (see also... 

Amongst these mitotic inhibitors are the Vinca alkaloids isolated from Vinca rosea, the periwinkle plant, of which vincristine and vinblastine are used chemically in the treatment of malignant disease, in particular acute leukaemia. Colchicine, used for many centuries in the treatment of gout, is isolated from the autumn crocus. Griseofulvin, and podophyllotoxin, are isolated from the resin of Podo-phyllum peltatum and used popularly in the treatment of warts. 

Taxol, isolated from Taxus brevefolia. Vincristine and Vinblastine isolated from Vinca rosea, and Taxotere, a semisynthetic form of Taxol, can induce Bcl-2 phosphorylation in tumor cell lines. The antiapoptotic potential of Bcl-2 has now been well established. But the biochemical mechanism of Bcl-2 action is still poorly understood (45). Haidar et al have shown that phosphorylated Bcl-2 can no longer prevent lipid peroxidation as required to protect cells from apoptosis (46). We have isolated and identified a novel polyphenol from Licorice that induces apoptosis, phosphorylating anti-apoptotic protein Bcl-2, causes G2/M cell cycle arrest in breast and prostate cancer cell lines (31). 

The alkaloid mixture from the extraction of Vinca rosea plants (as in vinblastine extraction) was chromatographed to give vincristine which was then converted to the sulfate, according to U.S. Patent 3,205,220. 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

The discovery of vinblastine and vincristine is one of the most intriguing examples of serendipity in scientihc research in recent years. In 1952, the Canadian medical researcher Robert Laing Noble (1910-90) received a package from his brother. Dr. Clark Noble, containing 25 leaves from the Madagascar periwinkle plant. Vinca rosea. Clark had received the leaves from one of his patients in Jamaica, who said that natives on the island often used the plant to control their diabetes when insulin was not available. Clark, who was retired, suggested that his brother study the plant for possible use as a drug for the treatment of diabetes. 

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. 

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. 

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.). 

Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle family (Vinca rosea). These compounds cause cells to stop at metaphase and inhibit assembly of microtubules, and likewise, failure of mitotic spindle formations. They inhibit synthesis of nucleic acids and proteins. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

Vincristine [vin KRIS teen] and vinblastine [vin BLAST een] are structurally-related compounds derived from the periwinkle plant, Vinca rosea. They are therefore referred to as the vinca alkaloids. A structurally related new (and less toxic) agent, vinorelbine [vye NO rel been] shows promise in the treatment of advanced non-small cell lung cancer. 

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. 

A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12. They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea (= Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the Aa-formyl analog, CIV, forms part of the dimeric alkaloid leurocristine (5, 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V. rosea and its dihydro-decarbomethoxy derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpa species (53). ( + )-Vincadif-formine (XCIII, 6, 74) has already been mentioned as the racemic form of (— )-6,7-dihydrotabersonine (Section II, O). It has been found in V. difformis and in Rhazya stricta (51b) where the (+) form also occurs. 

Vinblastine sulfate is the nonproprietary name assigned by the United States Adopted Names Council to the compound originally named vinca-leukoblastine sulfate1 s 3. It is the 1 1 sulfate salt of an alkaloid obtained from the plant Vinca rosea Linn. (Catharanthus roseus G. Don) of the family Apocynaceae, better known as Madagascar periwinkle. Frequently the name is abbreviated to VLB sulfate. It is also identified by the code numbers NSC-49812 and 29060-LE4. The elucidation of the molecular structure, stereochemistry, and absolute configuration of this interesting compound is fully documented in the literature5 7 8. 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

First studies were undertaken with Periwinkle plants from Jamaica. The roots, stems, and leaves all contain active material the leaves contain the highest proportion of activity, but in the seeds almost no activity is found.Today we know that four of the pure alkaloids, crystallised from extracts of Vinca rosea plants, namely vinblastine [(169), = vincaleukoblastine)], vincristine [(170), = leurocristine], vinleurosine [= leurosine, (183)], and vinrosidine [= leurosidine, (181)] show good effects in suppression of tumour growth. In the last decade about fifty-five alkaloids have been found in Vinca rosea extracts and tested for their pharmacological effects. Besides the four mentioned none of the... 

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