ALKALOIDS VINCA ALKALOIDS

PRESENTED BY- R. VIJAY KUMAR GUPTHA ROLL-10T21R0077 4th YEAR CMR COLLEGE OF PHARMACY GUDIED BY Mrs.SHARADHA dept,. of. pharmacognosy

Alkaloid Definition
Alkaloid: Alkaloids are hetero cyclic atoms which contains 1 or more nitrogens in its structure . these are organic products of natural or synthetic origin which are basic in nature. They also normally have a significant physiological action on humans and animals. Proto-alkaloid/ aminoalkaloid applied to compounds which lack one or more of the properties of typical alkaloids.

Other alkaloids which do not conform with the general definition are synthetic compounds not found in plants but are very closely related to natural alkaloids.

Alkaloid Description
Contains nitrogen - usually derived from an amino acid. Bitter tasting, generally white solids (exception - nicotine is a brown liquid). They give a precipitate with heavy metal iodides. Caffeine, a purine derivative, does not precipitate like most alkaloids. Alkaloids are basic - they form water soluble salts. Most alkaloids are well-defined crystalline substances which unite with acids to form salts. In plants, they may exist in the free state, as salts or as N-oxides. Occur in a limited number of plants. Nucleic acid exists in all plants, whereas, morphine exists in only one plant species.

Pharmacological Action & Uses

CNS Action: stimulants (caffeine) or depressants (morphine)
ANS: sympathomimetics (ephedrine) or sympatholytics (yohimbine, ergot alkaloids), parasympathomimetics (pilocarpine), anticholinergics (choline). USES: local anesthetics (cocaine), defibrillation (quinidine), anti- tumour agents (ellipticine), anti-malarial (quinine), anti- bacterials (berberine).

These actions lead to the extensive use of alkaloid containing herbs and drugs. Although some are used as galenicals (belladonna, datura, and henbane), most are used as starting materials for industrial extraction (morphine from poppy straw or opium, and quinine from Cinchona bark. 1.It is used for treating leukemia in children. 2.The drug is also used for treating hodgkins disease. 3.It has also shown good results in diabetic patients.

TYPES OF INDOLE ALKALOIDS

Vinca alkaloids
Vinca alkaloids are a set of anti-mitotic and anti-microtubule agents that were originally derived from the Periwinkle plant Catharanthus roseus. Vinca alkaloids are used in the treatment of cancer. They are a class of cell-cycle-specific cytotoxic drugs that work by inhibiting the ability of cancer cells to divide: Acting upon tubulin, they prevent it from forming into microtubules, a necessary component for cellular division. Vinca alkaloids are now produced synthetically and used as drugs in cancer therapy and as immunosuppressive drugs. These compounds include vinblastine,vincristine,vindesine, and vinorelbine.

 The vinca alkaloids are a subset of drugs derived from the Madagascar periwinkle plant. They were discovered in the 1950s by Canadian scientists, Robert Noble and Charles Beer. Vinca alkaloids have been used to treat diabetes, high blood pressure, and the drugs have even been used as disinfectants . However, the vinca alkaloids are most famous for being cancer fighters. At this time, there are four major vinca alkaloids in clinical use: vinblastine, vinorelbine, vincristine, and vindesine. All vinca alkaloids are administered intravenously (IV). They are eventually metabolized by the liver and excreted. The vinca alkaloids are cytotoxics they halt the division of cells and cause cell death. During cell division, vinca alkaloid molecules bind to the building blocks of a protein called tubulin, inhibiting its formation. Tubulin protein normally works in cells to create spindle fibers, (also called microtubules).

The leaves have acute base , rounded apex and have entire margin

The flowers are rose or violet or white or white with red eyes .

Catharanthus - Vinca

PHARMACOGNOSY OF VINCA ALKALOIDS

Biological Source

Aerial parts of Catharanthus roseus formerly known as Vinca rosea.

Family

Apocynaceae

Geographical Source

Endemic to Madagascar and India. Australia, also cultivated in Tropical Africa .

Morphology/Macroscop ical Characters

The leaves have acute base , rounded apex and have entire margin . The flowers are rose or violet or white or white with red eyes . The fruits have slight odour with bitter taste . The leaves have very strong and unpleasant odour and taste.

Chemistry

Vinca is rich in indole alkaloids particularly vincristine and vinblastine. Coupling of indole alkaloids such as catharanthine and vindoline produces the vinca alkaloids. Other alkaloids such as ajmalicine, lochnerine and serpentine are also found. Indole containing vinca alkaloids - Vinblastine, vincristine and vindoline.

Adulterants/Allied drugs/ Substitutes

Other Catharanthus species such as C. longifolius, C. trichophyllus and C. lanceus are known to contain vindoline type alkaloids. Vinca is useful in the herbal treatment of lymphomas. Vinblastine is used for the treatment of Hodgkins disease and nonHodgkins lymphomas while vincristine is used principally in the treatment of acute lymphocytic leukaemia.

Uses

Structure of vinca alkaloids

Vinca alkaloids have a common chemical structure consisting of an asymmetric dimer composed of a vindoline ring connected to a catarantine ring through carboncarbon bonds

STRUCTURE OF VINCRISTINE

General Information
Molecular Formula: C46H56N4O10 Molecular Weight: 824.97 Melting Point: 218-220C Clear liquid (taken by injection)

VINCRISTINE
Also known as Leurocristine, it is used to treat many different types of cancer. It has the best affinity for tubulin compared to the other Vinca alkaloids. It's the vinca alkaloid with longer terminal half-life and lower clearance. Does not pass the blood-brain barrier. Being carcinogenic, mutagenic and teratogenic, it causes mainly peripheral neurotoxicity, gastrointestinal toxicity (more rarely), but mild myelosuppression. Myelosuppression may be severe in races with mutations in the gene coding for the p-glycoprotein (requires a reduction of dose). Representation of the genes involved in the metabolism, transport, and downstream effects of the vinca alkaloid vincristine.

Natural Source of vincristine

Vincristine has two natural sources: Catharanthus roseus (Vinca rosea), the Madagascar periwinkle, and Tabernaemontana pachysiphon

This yield from the Madagascar periwinkle is less than 1g/g (.0003%)6

Synthesis of vincristine from vinblastine

H2CrO4

Ethyl Acetate
2 hours, -83- -25C 80-90% yield5

This is the easiest and most common method of synthesis, as well as one can give high yields

Synthetic Production

Discovered

in 2004 First route to make synthetic vincristine

Mechanism of action
Tubulinis 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

Stages of Mitosis
Interphase: Technically not part of mitosis, but rather encompasses stages G1, S, and G2 of the cell cycle which prepare the cell for mitosis. Prophase: Chromatin in nucleus condense; nucleolus disappears. Centrioles begin moving to opposite ends of the cell and fibers extend from the centromeres. Metaphase: Spindle fibers align the chromosomes along the middle of the cell nucleus. This line is referred to as the metaphase plate. Anaphase: The paired chromosomes separate at the kinetochores and move to opposite sides of the cell. Motion results from the physical interaction of polar microtubules. LYG

Stages of Mitosis (cont.)

Telophase: Chromatids arrive at opposite poles of cell, and new membranes form around the daughter nuclei. The chromosomes disperse.

Cytokinesis: Results when a fiber ring composed of a protein called actin around the center of the cell contracts, pinching the cell into two daughter cells, each with one nucleus.

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, Hodgkin's lymphoma 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 LAsparaginase. 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.

SIDE EFFECTS
The main side-effects of vincristine are peripheraLneuropathy, hyponatremia, constipation, and hair loss.

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent

VINBLASTINE
Initially named vincaleukoblastine, VLB, it differs from Vincristine only for one CH3 group at the vindoline ring and has similar pharmacokinetic characteristics. It can also inhibit angiogenesis. The main toxicity is non-cumulative myelosuppression, and then there is gastrointestinal toxicity, while neurotoxicity is rare.

Structure of the Vinblastine

Mechanism of action
Vinblastine is a vinca alkaloid and a chemical analogue of vincristine. It binds tubulin, thereby inhibiting the assembly of microtubules. Vinblastine treatment causes M phase specific cell cycle arrest by disrupting microtubule assembly and proper formation of the mitotic spindle and the kinetochore, each of which are necessary for the separation of chromosomes during anaphase of mitosis

Uses and side effects of vinblastine

Vinblastine [Velban] was the first of the Vincas to be used in the treatment of cancer. Useful in the treatment of: bladder and testicular cancers, Kaposis sarcoma, neuroblastoma and Hodgkins disease. Side effects : leukopenia, GI disturbances, cellulitis, phlebitis. Adverse effects Adverse effects of vinblastine include hair loss, loss of white blood cells and blood platelets, gastrointestinal problems, high blood pressure, depression, muscle cramps, vertigo and headaches.

Medications
Vincristine -Vials- Abic Oncovin - Vincristine Vials-Lily Velbe -Vinblastine Vials-Lily (Hodgkins disease ) Blastovine -Vinblastine-Teva Vials. All of these drugs present as sulphate salts.

VINORELBINE
Navelbine) is a relatively new vinca alkaloid discovered in the mid-1990s by the Pierre Fabre Company. It is a semi synthetic derivative of vinblastine. It is unique among the alkaloids because it has a very liposoluble structure, which ensures the complete depolymerization of microtubules. It can also be Structure administered orally.

of

the Vinorelbine

Vindesine
Vindesine [Eldisine] Useful in the treatment of: breast and lung cancer, leukemia. Side effects: immunodeficiency, anemia, myalgia, fatigue, mouth ulcers, GI upset.

Vinorelbine
Vinorelbine [Navelbine] Used in the treatment of: lung carcinoma, breast cancer. Side effects include: granulocytopenia, thrombocytopenia, myelosuppression, and less neurotoxicity than all of the other Vincas.

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