phytot h e r a p y Naturaly - PowerPoint Presentation

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phytot

h e r a p yNaturaly derived Phytothrapeutic anticancer agent

Grade 4- Spring semester 2020-2021Prof. Dr. Omji Porwal

Tishk International University FACULTY OF PHARMACY

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It has been estimated (2005) that over 60% of the anticancer drugs in current use are in some way derived from plants and microorganisms; marine products are in the process of evaluation. A successful anticancer drug should kill or incapacitate cancer cells without causing excessive damage to normal dividing cells. This ideal is difficult, or perhaps impossible, to attain and is why cancer patients frequently suffer unpleasant side-effects when undergoing treatment

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Plants in Cancer TreatmentPlant materials have been used in the treatment of malignant diseases for centuries; a comprehensive survey of the literature describing plants used against cancer listed over 1400 genera (Hartwell, 1967– 71, see Lloydia, 1971, 34, 427 for index). Recent phytochemical examination of plants which have a suitable history of use in folklore for the treatment of cancer has indeed often resulted in the isolation of principles with antitumour activity. Podophyllum was used over 2000 years ago by the ancient Chinese as an antitumour

drug, and resins from the root of the plant Podophyllum hexandrum (syn. P. emodi) and the related American species, the May-apple (P. peltatum) have yielded a number of lignans and their glycosides having antitumour activity

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Although the major constituents from these two species, podophyllotoxin and the peltatins, are unsuitable for systemic drug use, two semi-synthetic derivatives of podophyllotoxin, etoposide and teniposide, gave particularly good results in clinical trials. Etoposide is currently available for the treatment of small-cell lung cancer and testicular cancer, and teniposide is used in

paediatric cancers, though both compounds have a similar anticancer spectrum. Other podophyllotoxin-related analogues have been developed and tested.

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Podophyllotoxin itself may be used topically, and is most effective in the treatment of venereal warts. From the time of Galen (about ad 180),Very successful higher plant materials used in cancer chemotherapy are the alkaloids of Catharanthus roseus. Research on this plant, the Madagascan periwinkle, was stimulated by its mention in folklore, not as a cure for cancer, but in the treatment of diabetes

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Catharanthus roseus

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A number of bisindole alkaloids showing antileukaemic activity have subsequently been isolated and two of these, vincaleukoblastine (vinblastine) and leurocristine (vincristine), are now extracted commercially from Catharanthus roseus and used, either alone, or in combination with other forms of therapy for cancer treatment.

Another important, more recent, addition to the list of anticancer drugs is paclitaxel (Taxol), a diterpene derivative isolated initially from the bark of the Pacific Yew, Taxus brevifolia.

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Established Natural Products as Tumour InhibitorsThe tumour-inhibitory principles isolated in screening tests are usually new natural products, spanning a wide range of structural types.

Examples of these, subdivided into phytochemical groups, are listed in Table 27.1, and structures of the more promising chemicals which were subsequently evaluated in clinical tests.

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However, a number of the compounds isolated were, in fact, previously known natural products. These were presumably compounds which had not been subjected to rigorous testing for biological, particularly antitumour, activity. Amongst these are usnic acid, ellagic acid, the anthraquinone aloe-emodin, the quinones juglone and lapachol, pyrrolizidine alkaloids retronecine and monocrotaline, the

nitrophenanthrene aristolochic acid (see ‘Serpentary’), the bufadienolide hellebrigenin acetate, the Colchicum alkaloids colchicine, demecolcine and 3-demethylcolchicine (see ‘Colchicum’). Other known compounds that proved active but were rejected on terms of toxicity, low therapeutic index, etc. were the alkaloids of Senecio, indicine N-oxide from Heliotropium indicum and the cucurbitacins.

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New Natural Products with Antitumour Activity The systematic studies have also resulted in the isolation of many new natural products exhibiting antitumour activity, and a number of these were considered sufficiently active for clinical studies to be commenced (Table 27.1).

Tylocrebine, a phenanthroindolizidine alkaloid from Tylophora crebiflora was sufficiently active for further development, but in a clinical trial unmanageable CNS effects precluded continuation of the studies. Two bis-benzylisoquinoline alkaloids, thalicarpine from Thalictrum dasycarpum and tetrandrine from Cyclea peltata appeared particularly promising and were selected for development

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Plants Containing Anticancer Agents in Current UseCatharanthus Roseus: The Madagascan periwinkle, Catharanthus roseus, has been variously designated Vinca rosea and Lochnera rosea (Apocynaceae).Constituents: About 150 alkaloids have now been isolated from C. roseus; some, for example, ajmalicine,

lochnerine, serpentine and tetrahydroalstonine, occur in other genera of the family. Of particular interest is a group of about 20 bisindole alkaloids which contains those having antineoplastic activity, including leurocristine (vincristine) and vincaleukoblastine (vinblastine). Vinblastine is produced by couplin of the indole alkaloids catharanthine and vindoline, both of which occur free in the plant.

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Formation of 3′,4′-anhydrovinblastine from these monomers has been effected with peroxidase isozymes isolated from C. roseus suspension cultures and with commercial horseradish peroxidase (see J. P. Kutney, Nat. Prod. Rep., 1990, 7, 85–103). Vincristine is structurally similar to vinblastine, but has a formyl group rather than a methyl on the indole nitrogen in the vindoline-derived portion. Because these alkaloids are only minor constituents of the plant (vincristine is obtained in about 0.0002% yield from the crude drug), large quantities of raw material are required and chromatographic fractionations are extensively employed in the isolation procedures.

In addition, there is a growing demand for vincristine rather than vinblastine, but the plant produces a much higher proportion of vinblastine. Fortunately, it is now possible to convert vinblastine into vincristine either chemically, or via a microbiological N-demethylation using Streptomyces albogriseolus.

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Uses: Vinblastine is used mainly for the treatment of generalized Hodgkin’s disease, and non-Hodgkin’s lymphomas. Vincristine is used principally in the treatment of acute lymphocytic leukaemia in children. It has other applications for lymphomas, small-cell lung cancer, cervical and breast cancers. The semi-synthetic vindesine is also used in the treatment of acute lymphoid

leukaemia in children. Vincristine has a superior antitumour activity compared to vinblastine, but is more neurotoxic. Vinorelbine is a newer, orally active, semi-synthetic anhydro derivative of 8′-norvinblastine with a broader anticancer activity and lower neurotoxic side-effects than the other Catharanthus alkaloids.

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Podophyllum

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Podophyllum and Podophyllum ResinPodophyllum (Podophyllum Rhizome, May-apple Root, Wild Mandrake) consists of the dried rhizome and roots of Podophyllum peltatum (Berberidaceae, sometimes Podophyllaceae), a perennial herb common in moist shady situations in the eastern parts of Canada and the USA.

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Uses Podophyllum resin has long been used as a purgative but has largely been replaced by less drastic drugs. It has a cytotoxic action and is used as a paint in the treatment of soft venereal and other warts. Podophyllotoxin is also used for this purpose.

Etoposide (4′-demethylepipodophyllotoxin ethylideneglucoside) is a lignan derivative obtained semi-synthetically from podophyllotoxin and used in the treatment of small-cell lung cancer and testicular cancer as well as lymphomas and leukaemias. The water-soluble pro-drug etopophos (etoposide 4′-phosphate) is also available. The related thenylidene derivative teniposide has similar anticancer properties and though not as widely used as etoposide has value in paediatric neuroblastoma, lymphocytic leukaemia, and brain tumours in children (see H. Stähelin

and A. von Wartburg, Cancer Res., 1991, 51, 5–15).

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Taxus

Brevifolia

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Taxus Brevifolia and TaxolThe Pacific yew, Taxus brevifolia (Taxaceae) is a slow-growing shrub/tree found in the forests of North-West Canada (British Columbia) and the USA (Washington, Oregon, Montana, Idaho and N. California).

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UsesTaxol® (paclitaxel) is being used clinically in the treatment of ovarian cancers, breast cancers and non-small-cell lung cancer. It may also have potential value against other cancers. Taxotere® (docetaxel) is a side-chain analogue of taxol, which has also been produced by semi-synthesis from 10-deacetylbaccatin III.

It has improved water-solubility and is used in treatment of breast cancers.

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Thanks