VINCRISTINE

(3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate

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Vincristine (brand name, Oncovin), formally known as leurocristine, sometimes abbreviated “VCR”, is a vinca alkaloid from the Catharanthus roseus (Madagascar periwinkle), formerly Vinca rosea and hence its name. It is amitotic inhibitor, and is used in cancer chemotherapy. Vincristine is created by the coupling of indole alkaloids vindoline and catharanthine in the vinca plant.^[1]

Mechanism

Tubulin is a structural protein that polymerizes to microtubules. The cell cytoskeleton and mitotic spindle, among other things, are made of microtubules. Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow.

Uses

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkin’s lymphoma as part of the chemotherapy regimen CHOP, Hodgkin’s lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in acute lymphoblastic leukemia, and in treatment for nephroblastoma (Wilms tumor, a kidney tumor most common in young children). It is also used to induce remission in ALL with Dexamethasone and L-Asparaginase. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

The main side-effects of vincristine are peripheral neuropathy, hyponatremia, constipation, and hair loss.

Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) should avoid the taking of vincristine.^[2]

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.^[3] A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine andmethotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.^[4]

Having been used as a folk remedy for centuries, studies in the 1950s revealed that C. roseus contained 70 alkaloids, many of which are biologically active. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone marrow) led to its study in mice withleukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skelly-B defatting agent and an acid benzene extract led to a fraction termed “fraction A”. This fraction was further treated withaluminium oxide, chromatography, trichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.^[5]

Vincristine was approved by the United States Food and Drug Administration (FDA) in July 1963 as Oncovin. The drug was initially discovered by a team led by Dr. J.G. Armstrong, then marketed by Eli Lilly and Company.

Like LSD, the microtubule toxin vincristine allegedly causes not-unpleasant visual hallucinations in humans. Other side-effects of vincristine include depression, agitation, and insomnia. Very small doses are needed for the effects of LSD or vincristine, for example, these drugs are active at concentrations of 4.3E-7 M-1 vincristine and 1.0E-8 M-1 LSD.

Many researchers have favored the drug-receptor theory to explain drug-induced hallucinations, usually at the 5-HT2A receptor. In the drug-receptor theory, signal amplification takes place when one molecule of drug binds to a receptor, which activates G-proteins, which affects more proteins, thus signaling cascades explain how a small amount of LSD can lead to widespread changes in the cell.

Van Woerkom suggests instead that LSD binds an element of the cytoskeleton, in a fashion similar to colchicine or vinblastine, which directly bind tubulin. The amount of LSD needed to produce hallucinations is so vanishly small, that it seems hard to believe that a submicromolar dosage of LSD could act on a substrate as vast as the cytoskeleton. However, some microtubule inhibitors such as vincristine are effective at very low dosages. The potency of vincristine may partly explain the success of this drug as a chemotherapeutic drug.

Three generic drug makers supply vincristine in the United States – APP, Mayne, and Sicor (Teva).

External links

• Vincristine chemotherapy
• Vincristine and vinblastine
• Description and Natural History of the Periwinkle
• The Boger Route to (-)-Vindoline
• U.S. National Library of Medicine: Drug Information Portal – Vincristine

• Cytostatic Vinca alkaloids rosea L. Catharanthus roseus G.Don) are now well known anticancer and particularly useful. Given the small amount of vincristine in Catharanthus present, quite a number of ways of preparation have been proposed by chemists. Thus FR-A-2296418 describes the synthesis of vincristine by coupling Catha-ranthine and vindoline. Other laboratories have achieved the transformation of vinblastine vincristine oxidation under controlled conditions, very strict.
• FR-A-2210393 and US-A-3899493 perform the oxidation by chromic acid at -30, -90 ° C in a mixture of acetic acid-acetone or chloroform-acetic acid at -55 ° C.
• In U.S. 4,375,432, chromic compound is also used in acid medium at -65 ° C, -50 ° C in a medium based solvent THF. In addition, EP-A-37289 boasts an oxidation mixture ferrous salt, hydrogen peroxide, perchlorate in acetonitrile. ZA-A-82 08939 discloses a method with chromic acid and an ether-chloroform.
• HU-A-23638 offers diterbutylchromate in pelargonic acid, and finally EP-A-117861 gets vinblastinel transformation vincristine oxidant potassium permanganate in acetic acid medium. It is clear that these dimeric alkaloids are a valuable material because of their low levels in vegetable raw materials, and therefore the processes of synthesis or semi-synthesis performance are of extreme interest.

• Vincristine is used in cancer chemotherapy, particularly for the treatment of certain acute leukemias.
• This alkaloid is obtained mainly by extraction from leaves of Catharanthus Ro-seus (U.S. Patent No. 3,205,220) where it is accompanied by other alkaloids bis-Indo-holic, especially vinblastine.Vinblastine (I, R = CH _3), however, is present at a concentration much higher than that of vincristine and is therefore a precursor of choice for the semisynthesis of the latter.
• Several processes of vincristine from vinblastine were disclosed. We note in particular patents or patent applications include:

  • a) Belgian Patent 739,337 (Gedeon Richter) which describes a method for the oxidation of vinblastine vincristine in a mixture chromic acid, acetic acid and acetone.
  • b) Belgian Patent 823560 (Gedeon Richter) the oxidation is performed with oxygen in the presence of formic acid and of a catalyst based on platinum at room temperature.
  • c) European Patent Application 18231 (Gedeon Richter): is carried out by oxidation with chromic acid or an alkali metal dichromate in the presence of acetic anhydride and, optionally, of ethanol and an organic solvent immis target with water.
  • d) European Patent Application 37289 (Eli Lil-ly): the oxidation is effected by the perchlorate of iron (II) in the presence of hydrogen peroxide and acetonitrile.
• In addition, the European patent application 37. 290 discloses a process for the oxidation of vinblastine base with Na ₂ Cr ₂ O ₇ in the presence of sulfuric acid in tetrahydrofuran. This reaction led to -50 ° C, is achieved with a yield of 80-92% calculated for each estimation.
• Observed yields or purity of the products obtained characterizing the processes described above are, however, significant disadvantages.
• Frequently a secondary product formed is N-demethyl vinblastine need then reformulate for vincristine.

Thus Potier and Kutney obtained products with the C18’S-C2’R absolute configuration, which is critical for anti-tumor activity, by a coupling reaction of the N.sup.b -oxide of catharanthine, or its derivatives, with vindoline, in the presence of trifluoroacetic anhydride, followed by a reduction reaction. [See Potier et. al. J. Am. Chem. Soc. 98. 7017 (1976) and Kutney et. al. Helv. Chim. Acta, 59, 2858 (1976)].

The Potier and Kutney coupling process has disadvantages. The yields are not satisfactory except for the coupling of catharanthine N-oxide with vindoline and even there the preparative yield is low. While vindoline is the most abundant alkaloid of Vinca rosea and is thus readily available, the other possible components of the Potier-Kutney coupling process (catharanthine, allocatharanthine, voacangine,) are relatively inaccessible, costly, and they do not allow a wide range of structural variation of that component of the coupling process.

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• EP 0117861 B1
• clips
• The process of the present invention produces a simple vincristine, in quantity and purity requiring little or no additional purification by recrystallization or chromatography.
• [0009]
  The reagent used is oxidation permanganate ion dissolved in toluene or dichloromethane as solvent. An alternative consists in immobilizing the resin on a permanganate anion, for example a polymer such as polystyrene comprising ammonium groups. Solubilization can be achieved by the action of a complexing agent crown ether (“crown-ether”) of potassium permanganate.
• [0010]
  The permanganate anion can also be solubilized by preparing an ammonium salt or quaternary phosphonium corresponding which is soluble in methylene chloride or toluene. For this purpose, it is preferable to use potassium permanganate benzyltriethylammonium.
• [0011]
  Obtaining from vincristine vinblastine using a permanganate salt is unexpected since the potassium permanganate used in some acetone oxide derivatives of vinblastine at the portion of the molecule velbanamine (Kutney, Balsevich and Worth, Heterocycles, 11, 69, 1978). The N-methyl group of the vindoline part intact.
• [0012]
  The formation of N-CHO indoline skeleton on a bis-indole group vinblastine using a permanganate salt has never been reported.
• [0013]
  According to one embodiment of the method of the present invention, vinblastine, preferably in the form of sulphate, is treated in the presence of an organic acid such as acetic acid, with an excess of potassium permanganate dissolved in dichloromethane or toluene in the presence of “18-crown-6” or ether derivatives dibenzo-or di-cyclohexylcorrespondants. The reaction is conducted at a temperature between -40 ° C and -75 ° C and is preferably followed by thin layer chromatography. The reaction time generally ranges from 5 minutes to 3 hours.
• [0014]
  Potassium permanganate is preferably dissolved in dichloromethane and the oxidation reaction is then carried out at -70 ° C.
• [0015]
  The solubility of potassium permanganate is indeed substantially increased in the presence of a macrocyclic polyether as the “18-crown-6” ether (1, 4, 7, 10, 13, 16-hexaoxacy-clooctadécane) or derivative dibenzo – or corresponding dicyclohexyl-hexyl.
• [0016]
  The reaction mixture is then treated simultaneously by a mild reducing and alkaline. For this purpose, use is preferably an aqueous solution of bisulfite, disulfite or sodium metabisulfite and ammonia.
• [0017]
  The organic phase was separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases were concentrated in vacuo to give a residue containing 80-85% of base vincristine, a 90-95% yield.
• [0018]
  Alternatively, you can proceed with the extraction of the reaction mixture after reduction without conducting a simultaneous alkalinization. The acidic aqueous solution was then extracted with dichloromethane. This route is a novel process for purification of vincristine formed in the reaction medium.
• [0019]
  According to another embodiment of the present invention, vincristine is obtained by oxidation of vinblastine by reacting a quaternary ammonium permanganate. The ammonium cation is preferably benzyltriethylammonium group or benzyl trimethyl ammonium (see eg Angew. Chem., Intern. Ed. 13, 170, 1974). The reaction is carried out in 2 to 6 hours at -60 ° C in an inert solvent wherein the ammonium salt is soluble, and an acid, preferably an organic acid of low molecular weight. A mixture of dichloromethane and glacial acetic acid can be used. After treatment with a mild reducing agent in aqueous medium, the resulting acidic solution is extracted with dichloromethane, and the organic phase is made alkaline by washing with a basic aqueous solution and concentrated. Vincristine solvate is isolated with a yield higher than 90%.
• [0020]
  The latest variant of the method of the invention is particularly advantageous in terms of economic and technical.
• [0021]
  Purification or separation may be effected by crystallization and chromatography using techniques well known this from the crude product of the reaction. The product can also be lyophilized.
• [0022]
  In most cases, vincristine thus obtained can be converted directly into an addition salt with an organic or inorganic acid, preferably pharmaceutically acceptable. This salt is preferably a sulfate that may arise in a more or less solvated or hydrated.
• [0023]
  We can also prepare vincristine dissolved in a physiologically acceptable solvent and ready to be injected.
• [0024]
  In particular, vincristine sulfate is obtained by addition of H ₂ S0 ₄ to a solution of vincristine gross or recrystallized from ethanol, dissolved in a mixture of methylene chloride and anhydrous ethanol, partial removal in vacuo chloride methylene and crystallization.
• [0025]
  Vincristine sulfate thus obtained has a purity sufficient for use as a medicament, particularly in the form of injectable solutions.

Madagascar Periwinkle: Public Domain Illustration by Sydenham Edwards

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• vol. 101 no. 33
• > Takeshi Kuboyama,  11966–11970

Total synthesis of (+)-vincristine (2). TFA, trifluoroacetic acid or trifluoroacetyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene.

Stereocontrolled total synthesis of (+)-vincristine

• vol. 101 no. 33
• > Takeshi Kuboyama,  11966–11970

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see docstoc presentation

click below
Vincristine

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isolation

Kumar A, Patil D, Rajamohanan PR, Ahmad A (2013)

Isolation, Purification and Characterization of Vinblastine and Vincristine from Endophytic Fungus Fusarium oxysporumIsolated from Catharanthus roseus. PLoS ONE 8(9): e71805. doi:10.1371/journal.pone.0071805

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

see also

http://www.ncbi.nlm.nih.gov/pubmed/20209002

ALSO

large-scale isolation of native catharantine, vindoline and 3′,4′-anhydrovinblastine whereby the isolation of vincristine, vinblastine, leurosine and the corresponding desacetoxy, desacetyl and N-desmethyl derivatives in a manner known per se can also be accomplished.

For the isolation of the two monoindole alkaloids: vindoline and catharantine from the dried plant Vinca rosea L. Svoboda [J. Am. Pharm. Assoc. 48, (11), 659 (1959)] described a method, which can be accomplished only with a very modest yield. From 1 kg. of the dried plant–subjecting the whole plant to a suitable treatment–approximately 0.6 g. of vindoline and 0.05 g. of catharantine were obtained.

3′,4′-ANHYDROVINBLASTINE UNTIL NOW HAS NEITHER BEEN ISOLATED FROM THE PLANT Vinca rosea L. nor identified in it.

For the preparation of the diindole alkaloid components starting from the leaves of Vinca rosea L. there are more methods known in the art (U.S. Pat. nos. 3,097,137; 3,205,220; 3,225,030 and Hungarian Pat. Nos. 153,200; 154,715; 160,967 and 164,958 as well as Austrian Pat. Nos. 313,435, 313,485, Australian pat. No. 458,629 and Swiss Pat. No. 572,488 and British Pat Nos. 1,412,932, 1,382,460 corresponding to the preceding two patents). According to these known processes from 1 kg. of the dried leaves of Vinca rosea L. about 0.1 to 0.2 g. of leurosine can be obtained and vinblastine, vincristine and optionally the corresponding N-desmethyl, desacetyl and desacetoxy derivatives are also simultaneously isolated.

Further on it is well known that the synthetic catharantine and vindoline may be coupled by the Polonovszky reaction to give 3′,4′-anhydrovinblastine which can thereafter be epoxidized to leurosine [Potier et al. Tetrahedron Letters 3945 (1976); DT-OS 25 58,124; Helv. Chim. Acta 59, 2858 (1976); Heterocycles 4, 997 (1976), Belgian patent specification No. 842,200 equivalent to U.S. patent application Ser. No. 582,372]. Leurosine itself has a valuable tumour growth inhibiting activity and the N-desmethyl-N-formyl derivative thereof is the most promising substance against leukemia (Hungarian Pat. No. 165,986 equivalent to U.S. patent application Ser. No. 422,100, and Austrian Pat. No. 332,566 which has issued as British Pat. No. 1,412,932).