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This Little Known Chinese Herb Kills 12,000 Cancer Cells For Every Healthy Cell

March 27, 2014 5:13 am / 5 Comments on This Little Known Chinese Herb Kills 12,000 Cancer Cells For Every Healthy Cell

WORMWOOD PLANT

This Little Known Chinese Herb Kills 12,000 Cancer Cells For Every Healthy Cell

collective-evolution.com

Today, odds are that you have had/have cancer, or know somebody who does. In Canada, approximately one million Canadians that were alive at…

read all at

http://www.collective-evolution.com/2014/03/26/this-little-known-chinese-herb-kills-12000-cancer-cells-for-every-healthy-cell/

http://spartanoftruth.wordpress.com/2014/03/26/this-little-known-chinese-herb-kills-12000-cancer-cells-for-every-healthy-cell/

http://peoplestrusttoronto.wordpress.com/2014/03/26/this-little-known-chinese-herb-kills-12000-cancer-cells-for-every-healthy-cell/

A little known Chinese herb might be eligible for the growing list of cancer killers via alternative methods of treatment. According to studies published in Life Sciences, Cancer Letters and Anticancer Drugs, artemesinin, a derivative of the wormwood plant commonly used in Chinese medicine, can kill off cancer cells, and do it at a rate of 12,000 cancer cells for every healthy cell.

Artemisinin is currently FDA approved for the treatment of malaria, it’s very safe and easy to use. It’s inexpensive and works on all cancers but has yet to find it’s way into the mainstream. It’s really time to move beyond just radiation, surgery and chemotherapy for the treatment of cancer.

artemisinin

“Artemisinin reacts with iron to form free radicals that kill cells. Since cancer cells uptake relatively larger amounts of iron than normal cells, they are more susceptible to the toxic effect of artemisinin. In previous research, we have shown that artemisinin is more drawn to cancer cells than to normal cells. In the present research, we covalently attached artemisinin to the iron-carying plasma glycoprotein transferrin.Transferrin is transported into the cells via receptor-mediated endocytosis and cancer cells express significantly more transferrin receptors on their cell surface and endocytose more transferrin than normal cells. Thus, we hypothesize that by tagging artemisinin to transferrin, both iron and artemisinin would be transported into cancer cells in one package. Once inside a cell, iron is released and can readily react with artemisinin close by tagged to the transferrin. This would enhance the toxicity and selectivity of artemisinin towards cancer cells. We found that holotransferrin-tagged artemisinin, when compared with artemisinin, was very potent and selective in killing cancer cells. Thus, this ‘tagged-compound’ could potentially be developed into an effective chemotherapeutic agent for cancer treatment.”

Wormwood

Other common name(s): absinthium, absinth wormwood

Scientific/medical name(s): Artemisia absinthium

Description

Wormwood is a shrubby perennial plant whose upper shoots, flowers, and leaves are used in herbal remedies and as a bitter flavoring for alcoholic drinks. It is native to Europe, northern Africa, and western Asia, and now also grows in North America.

Overview

Available scientific evidence does not support claims that wormwood is effective in treating cancer, the side effects of cancer treatment, or any other conditions. The plant contains a volatile oil with a high level of thujone (see Thuja). There are reports that taking large doses of wormwood internally can cause serious problems with the liver and kidneys. It can also cause nausea, vomiting, stomach pain, headache, dizziness, seizures, numbness of the legs and arms, delirium, and paralysis.

Wormwood, or Artemisia absinthium, should not be confused with sweet wormwood, or Artemisia annua. Although wormwood is related to sweet wormwood, they are used in different ways. Extracts of sweet wormwood have been used in traditional herbal medicine, and an active ingredient, artemisinin, is now used in conventional medical treatment of malaria.

How is it promoted for use?

Wormwood is promoted as a sedative and anti-inflammatory. There are also claims that it can treat loss of appetite, stomach disorders, and liver and gallbladder complaints. In folk medicine it is used for a wide range of stomach disorders, fever, and irregular menstruation. It is also used to fight intestinal worms. Externally, it is applied to poorly healing wounds, ulcers, skin blotches, and insect bites. It is used in Moxibustion treatments for cancer (seeMoxibustion). Available scientific evidence does not support these claims.

What does it involve?

Wormwood is taken in small doses for a short period of time, usually a maximum of 4 weeks. It is available as a capsule and as a liquid that can be added to water to make a tincture. The whole herb is sometimes brewed as a tea. Wormwood oil, washes, or poultices can also be used on the skin. Although pure wormwood is not available, “thujone-free” wormwood extract has been approved by the US Food and Drug Administration (FDA) for use in foods and as a flavoring in alcoholic drinks such as vermouth.

What is the history behind it?

Artemisia absinthium was used by Hippocrates, and the earliest references to wormwood in Western civilization can be found in the Bible. Extract of wormwood was also used in ancient Egypt. The herb is mentioned often in first-century Greek and Roman writings and reportedly was placed in the sandals of Roman soldiers to help soothe their sore feet. It was taken as a treatment for tapeworms as far back as the Middle Ages.

In 1797, Henri Pernod developed absinthe, an alcoholic drink containing distilled spirits of wormwood, fennel, anise and sometimes other herbs. Absinthe became very popular in Europe and the United States in the nineteenth century. It was eventually banned in several countries in the early twentieth century due to its purported ill effects and addictive qualities. More recent analysis has suggested that, when properly prepared and distilled, the thujone content in these drinks was very low. It appears more likely that the addictiveness and other ill effects of absinthe were due to its alcohol content, which is around 60% to 85%. Varying additives or impurities from different distillers may have also produced some of these effects. Even though absinthe is illegal in some countries, various types can be found in some European countries. However, their thujone content is strictly limited. Wormwood is also an ingredient in vermouth and other drinks.

What is the evidence?

Available scientific studies do not support the use of wormwood for the treatment of cancer or the side effects of conventional cancer treatment. There is not enough evidence available to support its use for other conditions. Wormwood oil has been tested in laboratory studies and appears to inhibit the growth of some fungi. However, human tests have not been completed.

Some derivatives of Artemisia annua, or sweet wormwood, a relative of wormwood, have been shown to be effective in the treatment of malaria. In fact, the World Health Organization approved artemisinin for use against malaria in Africa in 2004. These extracts also show some promise in laboratory studies as cancer treatment drugs. Further studies are required to find out whether the anti-cancer results apply to people. It is important to remember that extracted compounds are not the same as the whole herb, and study results are not likely to show the same effects.

Are there any possible problems or complications?

This product is sold as a dietary supplement in the United States. Unlike companies that produce drugs (which must be tested before being sold), the companies that make supplements are not required to prove to the Food and Drug Administration that their supplements are safe or effective, as long as they don’t claim the supplements can prevent, treat, or cure any specific disease.

Some such products may not contain the amount of the herb or substance that is on the label, and some may include other substances (contaminants). Actual amounts per dose may vary between brands or even between different batches of the same brand. In 2007, the FDA wrote new rules to improve the quality of manufacturing for dietary supplements and the proper listing of supplement ingredients. But these rules do not address the safety of the ingredients or their effects on health.

Most such supplements have not been tested to find out if they interact with medicines, foods, or other herbs and supplements. Even though some reports of interactions and harmful effects may be published, full studies of interactions and effects are not often available. Because of these limitations, any information on ill effects and interactions below should be considered incomplete.

Wormwood should be avoided, especially by women who are pregnant or breast-feeding, by people who have had seizures, and by those with ulcers or stomach irritation. Thujone, a component of wormwood, is known to cause muscle spasms, seizures, and hallucinations if taken internally. In high doses it is known to damage the liver and the kidneys.

Because of its thujone content, large doses of wormwood taken internally can lead to vomiting, stomach and intestinal cramps, headaches, dizziness, nervous system problems, and seizures. Wormwood can also lead to liver failure. The New England Journal of Medicine reported that a man who ordered essential oil of wormwood over the Internet, thinking he had purchased absinthe, suffered liver failure shortly after drinking the oil. Wormwood may also make seizures more likely and may interfere with the anti-convulsant effects of medicines such as phenobarbital.

The plant is a relative of ragweed and daisies. Those with allergies to these types of plants may also be allergic to wormwood. Contact with wormwood can cause rash in some people.

Relying on this type of treatment alone and avoiding or delaying conventional medical care for cancer may have serious health consequences.

Replacing insulin though stem cell-derived pancreatic cells under the skin

March 27, 2014 3:54 am / Leave a comment

Islet of Langerhans

Microscopic view of Islet of Langerhans in the pancreas. Beta cells in the Islets are responsible for producing insulin

Sanford-Burnham and UC San Diego School of Medicine scientists have shown that by encapsulating immature pancreatic cells derived from human embryonic stem cells (hESC), and implanting them under the skin in animal models of diabetes, sufficient insulin is produced to maintain glucose levels without unwanted potential trade-offs of the technology. The research suggests that encapsulated hESC-derived insulin-producing cells hold great promise as an effective and safe cell-replacement therapy for insulin-dependent diabetes. “Our study critically evaluates some of the potential pitfalls of using stem cells to treat insulin-dependent diabetes,” said Pamela Itkin-Ansari, Ph.D., adjunct assistant professor in the Development, Aging, and Regenerative Program at Sanford-Burnham, with a joint appointment at UC San Diego. – See more at: http://beaker.sanfordburnham.org/2014/03/replacing-insulin-though-stem-cell-derived-pancreatic-cells-under-the-skin/#sthash.GDnpkm3h.dpuf

See more at: http://beaker.sanfordburnham.org/2014/03/replacing-insulin-though-stem-cell-derived-pancreatic-cells-under-the-skin/

Licorice मुलेठी, 甘草, شیرین بیان Inhibits 92% of Breast Cancer Cells & Slows Growth by 83% in Vivo:

March 27, 2014 3:34 am / 1 Comment on Licorice मुलेठी, 甘草, شیرین بیان Inhibits 92% of Breast Cancer Cells & Slows Growth by 83% in Vivo:

Licorice Inhibits 92% of Breast Cancer Cells & Slows Growth by 83% in Vivo:

Isoliquiritigenin

Isoliquiritigenin, a natural licorice compound, inhibited 92% of human breast cancer cells (both ER+ and triple-negative) in vitro after 48 hours of treatment in this new study. When given to mice, it resulted in breast tumors 83% smaller than untreated mice after 25 days.

Researchers discovered this licorice compound was not only cytotoxic to the breast cancer cells but also profoundly reduced the key angiogenesis factor VEGF by up to 85%, thus disabling the cancer from connecting new blood supplies to feed the tumors. Licorice is a powerful herb which has already shown strong activity against prostate cancer, colon cancer, cervical cancer, leukemia and others in lab studies.

Although used as a candy in the West, licorice root has been used as a medicinal herb for centuries in traditional Chinese and Ayurvedic medicine for treating asthma, allergies, stomach ache, insomnia, inflammation, viral infection and many other conditions. Licorice is also a proven adrenal booster, which makes it a great alternative to caffeine in fighting fatigue and boosting energy levels.

Bottom line: this super-herb could be a great addition to a healthy diet centered on organic vegetables, fruit and whole foods. And if you want to limit your sugar intake, it’s simple to make as a tea. read all this at

http://www.ncbi.nlm.nih.gov/pubmed/23861918

Liquorice or licorice (/ˈlɪk(ə)rɪʃ/ lik-(ə-)rish or /ˈlɪk(ə)rɪs/ lik-(ə-)ris)^[2] is the root of Glycyrrhiza glabra from which a somewhat sweet flavor can be extracted. The liquorice plant is a legume that is native to southern Europe and parts of Asia. It is not botanically related to anise, star anise, or fennel, which are sources of similar flavouring compounds. The word ‘liquorice’/’licorice’ is derived (via the Old French licoresse), from the Greek γλυκύρριζα (glukurrhiza), meaning “sweet root”,^[3] from γλυκύς (glukus), “sweet”^[4] + ῥίζα (rhiza), “root”,^[5]^[6] the name provided by Dioscorides.^[7]

Description

It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 cm (3–6 in) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (⅓–½ in) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 cm (1 in) long, containing several seeds.^[8]The roots are stoloniferous.^[9]

Chemistry

The scent of liquorice root comes from a complex and variable combination of compounds, of which anethole is the most minor component (0-3% of total volatiles). Much of the sweetness in liquorice comes from glycyrrhizin, which has a sweet taste, 30–50 times the sweetness of sugar. The sweetness is very different from sugar, being less instant and lasting longer.

The isoflavene glabrene and the isoflavane glabridin, found in the roots of liquorice, are xenoestrogens.^[10]^[11]

A, phase I metabolites of ILG formed during incubation with rat liver microsomes and NADPH. Based on accurate mass measurements, HPLC retention times, MS/MS analyses, and comparison with data reported by Guo et al. (18), the structures of metabolites M1, M2, M3, M4, M5, M6, and M7 were assigned as liquiritigenin, 7,8,4′-trihydroxychalcone, sulfuretin, 7,3′,4′-trihydroxychalcone, davidigenin, trans-6,4′-dihydroxyaurone, and cis-6,4′-dihydroxyaurone, respectively. B, structures of ILG glucuronide conjugates formed by rat liver microsomes in the presence of UDPGA.

Cultivation and uses

Liquorice grows best in deep valleys, well-drained soils, with full sun, and is harvested in the autumn, two to three years after planting.^[8] Countries producing liquorice include Iran, Afghanistan, the People’s Republic of China, Pakistan, Iraq, Azerbaijan, Uzbekistan, Turkmenistan and Turkey.^[12]

The world’s leading manufacturer of liquorice products is M&F Worldwide, which manufactures more than 70% of the worldwide liquorice flavors sold to end-users.^[13]

Tobacco

Most liquorice is used as a flavoring agent for tobacco. For example, M&F Worldwide reported in 2011 that approximately 63% of its liquorice product sales are to the worldwide tobacco industry for use as tobacco flavor enhancing and moistening agents in the manufacture of American blend cigarettes, moist snuff, chewing tobacco and pipe tobacco.^[12] American blend cigarettes made up a larger portion of worldwide tobacco consumption in earlier years,^[14] and the percentage of liquorice products used by the tobacco industry was higher in the past. M&F Worldwide sold approximately 73% of its liquorice products to the tobacco industry in 2005,^[15] and a consultant to M&F Worldwide’s predecessor company stated in 1975 that it was believed that well over 90% of the total production of liquorice extract and its derivatives found its way into tobacco products.^[16]

Liquorice provides tobacco products with a natural sweetness and a distinctive flavor that blends readily with the natural and imitation flavoring components employed in the tobacco industry, represses harshness, and is not detectable as liquorice by the consumer.^[16] Tobacco flavorings such as liquorice also make it easier to inhale the smoke by creating bronchodilators, which open up the lungs.^[17] Chewing tobacco requires substantially higher levels of liquorice extract as emphasis on the sweet flavor appears highly desirable.^[16]

Food and candy

Medicine

Foliage

Glycyrrhiza glabra from Koehler’sMedicinal-Plants

References

“Glycyrrhiza glabra information from NPGS/GRIN”. http://www.ars-grin.gov. Retrieved 6 March 2008.
licorice. Merriam-Webster’s Medical Dictionary, © 2007 Merriam-Webster, Inc.
γλυκύρριζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
γλυκύς, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
ῥίζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus<
liquorice, on Oxford Dictionaries
google books Maud Grieve, Manya Marshall – A modern herbal: the medicinal, culinary, cosmetic and economic properties, cultivation and folk-lore of herbs, grasses, fungi, shrubs, & trees with all their modern scientific uses, Volume 2 Dover Publications, 1982 & Pharmacist’s Guide to Medicinal Herbs Arthur M. Presser Smart Publications, 1 Apr 2001 2012-05-19
Huxley, A., ed. (1992). New RHS Dictionary of Gardening. ISBN 0-333-47494-5
Brown, D., ed. (1995). “The RHS encyclopedia of herbs and their uses”. ISBN 1-4053-0059-0
Somjen, D.; Katzburg, S.; Vaya, J.; Kaye, A. M.; Hendel, D.; Posner, G. H.; Tamir, S. (2004). “Estrogenic activity of glabridin and glabrene from licorice roots on human osteoblasts and prepubertal rat skeletal tissues”. The Journal of Steroid Biochemistry and Molecular Biology 91(4–5): 241–246. doi:10.1016/j.jsbmb.2004.04.008. PMID 15336701.
Tamir, S.; Eizenberg, M.; Somjen, D.; Izrael, S.; Vaya, J. (2001). “Estrogen-like activity of glabrene and other constituents isolated from licorice root”. The Journal of steroid biochemistry and molecular biology78 (3): 291–298. doi:10.1016/S0960-0760(01)00093-0.PMID 11595510.
M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2010.
M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2001.
Erik Assadourian, Cigarette Production Drops, Vital Signs 2005, at 70.
M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2005.
Marvin K. Cook, The Use of Licorice and Other Flavoring Material in Tobacco (Apr. 10, 1975).
Boeken v. Phillip Morris Inc., 127 Cal. App. 4th 1640, 1673, 26 Cal. Rptr. 3d 638, 664 (2005).
[1] the online Dutch food composition database]
“Right good food from the Ridings”. AboutFood.com. 25 October 2007.
“Where Liquorice Roots Go Deep”. Northern Echo. Retrieved 9 December 2008.
Licorice Calories
Liu Q, Garner P, Wang Y, Huang B, Smith H (2008). “Drugs and herbs given to prevent hepatotoxicity of tuberculosis therapy: systematic review of ingredients and evaluation studies”. BMC Public Health (Systematic review) 8: 365. doi:10.1186/1471-2458-8-365. PMC 2576232.PMID 18939987.
Sato, H; Goto, W; Yamamura, J; Kurokawa, M; Kageyama, S; Takahara, T; Watanabe, A; Shiraki, K (May 1996). “Therapeutic basis of glycyrrhizin on chronic hepatitis B.”. Antiviral Research 30 (2-3): 171–7.doi:10.1016/0166-3542(96)00942-4. PMID 8783808.
van Rossum, TG; Vulto, AG; de Man, RA; Brouwer, JT; Schalm, SW (March 1998). “Review article: glycyrrhizin as a potential treatment for chronic hepatitis C.” (PDF). Alimentary Pharmacology & Therapeutics12 (3): 199–205. doi:10.1046/j.1365-2036.1998.00309.x.PMID 9570253.
Chien, CF; Wu, YT; Tsai, TH (January 2011). “Biological analysis of herbal medicines used for the treatment of liver diseases.”. Biomedical Chromatography 25 (1-2): 21–38. doi:10.1002/bmc.1568.PMID 21204110.
Yasui, S; Fujiwara, K; Tawada, A; Fukuda, Y; Nakano, M; Yokosuka, O (December 2011). “Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis.”. Digestive Diseases and Sciences56 (12): 3638–47. doi:10.1007/s10620-011-1789-5.PMID 21681505.
Reuter, J; Merfort, I; Schempp, CM (2010). “Botanicals in dermatology: an evidence-based review.”. American Journal of Clinical Dermatology11 (4): 247–67. doi:10.2165/11533220-000000000-00000.PMID 20509719.
Hasani-Ranjbar, S; Nayebi, N; Moradi, L; Mehri, A; Larijani, B; Abdollahi, M (2010). “The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review.”. Current pharmaceutical design 16 (26): 2935–47. PMID 20858178.
Callender, VD; St Surin-Lord, S; Davis, EC; Maclin, M (April 2011). “Postinflammatory hyperpigmentation: etiologic and therapeutic considerations.”. American Journal of Clinical Dermatology 12 (2): 87–99. doi:10.2165/11536930-000000000-00000. PMID 21348540.
Leyden, JJ; Shergill, B; Micali, G; Downie, J; Wallo, W (October 2011). “Natural options for the management of hyperpigmentation.”. Journal of the European Academy of Dermatology and Venereology 25 (10): 1140–5. doi:10.1111/j.1468-3083.2011.04130.x. PMID 21623927.
Kannappan, R; Gupta, SC; Kim, JH; Reuter, S; Aggarwal, BB (October 2011). “Neuroprotection by spice-derived nutraceuticals: you are what you eat!” (PDF). Molecular Neurobiology 44 (2): 142–59.doi:10.1007/s12035-011-8168-2. PMC 3183139.PMID 21360003.
Gazzani, G; Daglia, M; Papetti, A (April 2012). “Food components with anticaries activity.”. Current Opinion in Biotechnology 23 (2): 153–9.doi:10.1016/j.copbio.2011.09.003. PMID 22030309.
Messier, C; Epifano, F; Genovese, S; Grenier, D (January 2012). “Licorice and its potential beneficial effects in common oro-dental diseases.”. Oral Diseases 18 (1): 32–9. doi:10.1111/j.1601-0825.2011.01842.x. PMID 21851508.
Shibata, S (October 2000). “A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice.”. Yakugaku Zasshi 120 (10): 849–62. PMID 11082698.
Fiore, C; Eisenhut, M; Ragazzi, E; Zanchin, G; Armanini, D (July 2005). “A history of the therapeutic use of liquorice in Europe.”. Journal of Ethnopharmacology 99 (3): 317–24. doi:10.1016/j.jep.2005.04.015.PMID 15978760.
Ming, LJ; Yin, AC (March 2013). “Therapeutic effects of glycyrrhizic acid.”. Natural Product Communications 8 (3): 415–8.PMID 23678825.
Bensky, Dan; et al. (2004). Chinese Herbal Medicine: Materia Medica, Third Edition. Eastland Press. ISBN 0-939616-42-4.
Das, S. K.; Das, V.; Gulati, A. K.; Singh, V. P. (1989). “Deglycyrrhizinated liquorice in aphthous ulcers”. The Journal of the Association of Physicians of India 37 (10): 647. PMID 2632514.
Krausse, R.; Bielenberg, J.; Blaschek, W.; Ullmann, U. (2004). “In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites”. Journal of Antimicrobial Chemotherapy 54 (1): 243–246.doi:10.1093/jac/dkh287. PMID 15190039.
Olukoga, A; Donaldson, D (June 2000). “Liquorice and its health implications.”. The Journal of the Royal Society for the Promotion of Health 120 (2): 83–9. doi:10.1177/146642400012000203.PMID 10944880.
Armanini, D; Fiore, C; Mattarello, MJ; Bielenberg, J; Palermo, M (September 2002). “History of the endocrine effects of licorice.”.Experimental and Clinical Endocrinology & diabetes 110 (6): 257–61.doi:10.1055/s-2002-34587. PMID 12373628.

National Institute of Health – Medline
PDRhealth.com – Profile of Deglycyrrhizinated Licorice (DGL)
Chemical & Engineering News article on Licorice
Non-profit site on the health aspects of licorice/liquorice
Medical use of irritation on chest

Brisbane scientists make cancer treatment breakthrough

March 25, 2014 1:08 am / 1 Comment on Brisbane scientists make cancer treatment breakthrough

Are you serious 5-10 years !! They are doing this in Germany for all cancers – it’s called immunotherapy. Again more money going to research on research already done !! and again my knickers are in a twist – actually think it may be a wedgie by now – he he he. However all silliness aside I do hope more people are starting to see the bigger picture of why we are not progressing forward

Brisbane scientists make cancer treatment breakthrough

abc.net.au

Queensland medical researchers say they have made a remarkable discovery that could lead to improved cancer treatments.

http://www.abc.net.au/news/2014-03-24/brisbane-scientists-make-cancer-treatment/5342420

Onion extract slows colon cancer growth just as effectively as chemo drug

March 17, 2014 9:18 am / 1 Comment on Onion extract slows colon cancer growth just as effectively as chemo drug

cancer

(NaturalNews) Researchers have just discovered that flavonoids extracted from common onions slow the rate of colon cancer growth in mice just as effectively as a chemotherapy drug. And while the mice on chemo saw their LDL cholesterol go up (a possible side effect of the drug), the mice on onion extract actually saw their LDL levels drop.

Onion flavonoids slow colon tumor growth by 67% in vivo

Learn more: http://www.naturalnews.com/044318_onion_extract_colon_cancer_chemotherapy_drug.html##ixzz2wD3udzfF

http://www.naturalnews.com/044318_onion_extract_colon_cancer_chemotherapy_drug.html#

Garden Cress Extract Kills 97% of Breast Cancer Cells in Vitro

February 11, 2014 3:56 am / 58 Comments on Garden Cress Extract Kills 9758 of Breast Cancer Cells in Vitro

garden cress

Garden Cress Extract Kills 97% of Breast Cancer Cells in Vitro: Garden cress, like broccoli, is a cruciferous-family vegetable but is unique because it contains very high amounts of BITC (benzyl isothiocyanate) which has emerged as a powerful anti-cancer compound. In this study, BITC was seen to kill 97% of ER- breast‪cancer‬ cells (MDA-MB-231) after 24 hours of treatment. For comparison, the same dose of sulforaphane from ‪‎broccoli‬ killed only 75% of the cancer cells.

In other research, BITC has been found to slow the rate of breast cancer metastasizing by 86% and when given to mice, resulted in breast tumors 53% smaller than in untreated mice. BITC is now being intensively studied for a variety of cancers and has been shown in lab studies to be active against melanoma, glioma, prostate cancer, lung cancer, ovarian cancer, pancreatic cancer and others. Garden ‪‎cress‬ is one of the best sources of BITC. Other good sources include cabbage, Indian cress, Japanese radish (in particular Karami daikon) and, quite surprisingly, papaya seeds. As with other‪cruciferous‬ vegetables, the best way to eat cress is raw in order to maximize the delivery of BITC.

http://www.ncbi.nlm.nih.gov/pubmed/17121941

http://extension.usu.edu/files/publications/publication/HG_Garden_2006-05.pdf

and

http://nopr.niscair.res.in/bitstream/123456789/12732/1/IJNPR%202(3)%20292-297.pdf

BITC

Botanical name: Lepidium sativum L.
Family: Brassicaceae = Cruciferae
Common names. English: cress, common cress, garden cress, land cress, pepper cress; Spanish: mastuerzo, mastuerzo hortense, lepidio, berro de jardín (Spain), berro de sierra, berro hortense (Argentina), escobilla (Costa Rica); Catalan: morritort, morrisà, Portuguese and Galician: masturco, mastruco, agrião-mouro, herba do esforzo; Portuguese: mastruco do Sul, agrião (Brazil); Basque: buminka, beatzecrexu

Synonyms/Common Names/Related Substances:

Alpha-linolenic acid (ALA), agrião (Portuguese), agrião-mouro (Portuguese, Galician), beatzecrexu (Basque), berro de jardín (Spanish), berro de tierra (Spanish), berro hortense (Spanish), benzyl isothiocyanate (BITC), Brassicaceae (family), bran, buminka (Basque), common cress, cress, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), escobilla (Spanish), endosperm, fiber, garden cress seed oil (GCO), garden pepper grass, glucosinolates, glutamic acid, herba do esforzo (Portuguese, Galician), hurf (Arabic), indoles, isothiocyanates, kardamon (Greek), land cress, linoleic acid (LA), lectin, lepidio (Spanish), Lepidium sativium, Lepidium sativum, leucine, mastruco (Portuguese, Galician), mastruco do sul (Portuguese), mastuerzo (Spanish), mastuerzo hortense (Spanish), methanol, morrisá (Catalan), morritort (Catalan), nasturtium (Latin), nasum torcere (Latin), omega-3 fatty acid, pepper cress, pepper grass, pepperwort, sulforaphane, tuffa’ (Arabic), turehtezuk (Persian), water cress, whole meal.
Combination product example: SulforaWhite (a liposomal preparation that contains Lepidium sativum sprout extract, glycerin, lecithin, phenoxyethanol, and water).

Garden cress [commonly known as aliv in Marathi or halim in Hindi] is a green, cool-season perennial plant used as a leafy vegetable, typically used as a garnish. Undisturbed, the plant can grow to a height of two feet with minimal maintenance. When mature, garden cress produces white or light-pink flowers, and small seed pods. It has long leaves at the bottom of the stem and small, bright-green, feather-like leaves arranged on opposite sides of its stalks at the top.

Garden Cress, also called Pepper Wort, is an herb that is botanically known as Lepidium Sativum. It is referred to as ‘Aliv’ in Marathi and ‘Halim’ in Hindi. Belonging to the family Cruciferae, it is grown in all parts of India and is often used in the Indian cuisine. The leaves, roots, as well as seeds of this plant are used in cooking as they are extremely nutritious and also therapeutic in nature. The flowers of this plant are either white or light-pink in color.

This herb is the best source of iron and is hence recommended in the treatment of iron-deficiency anemia. It is also rich in folate, calcium, ascorbic acid, tocopherol, and beta-carotene. Garden Cress seeds are loaded with not just protein, but also linoleic and arachidic fatty acids. Since they contain phytochemicals that mimic estrogen to some extent, intake of these seeds is known to regulate menstruation and stimulate milk production in lactating mothers. That is precisely why women are given foods containing Garden Cress following childbirth.

The blood-purifying as well as antioxidant properties of this amazing plant are well documented. Hence, its regular consumption can greatly help to boost one’s immunity and prevent a gamut of diseases. It acts as a general tonic and can also help to increase the libido naturally. Since the testae of these seeds contain mucilage, they are invaluable in the management of both dysentery and constipation. The whole plant, along with its seeds, is said to be good for the eyes too. Hence, it is advisable to add it raw to salads, sandwiches, and chutneys, or to simply use it as a garnish along with coriander leaves for any food item.

Pregnant women should avoid taking Garden Cress in any form because it has the ability to induce uterine contractions and thereby trigger a spontaneous abortion. Also, since it is goitrogenic in nature, it may not be suitable for patients suffering from hypothyroidism. The oil derived from Garden Cress seeds is edible and can therefore be used as a cooking medium; however, some people may experience symptoms of indigestion due to its use. Such individuals should discontinue using this oil or mix it with some other edible oil, so as to dilute it and reduce its adverse effects.

Cress (Lepidium sativum), sometimes referred to as garden cress to distinguish it from similar plants also referred to as cress, is a rather fast-growing, edible herb. Garden cress is genetically related to watercress and mustard, sharing their peppery, tangy flavor and aroma. In some regions, garden cress is known as mustard and cress, garden pepper cress, pepperwort pepper grass, or poor man’s pepper.^[1]^[2]

This annual plant can reach a height of 60 cm (~24 inches), with many branches on the upper part. The white to pinkish flowers are only 2 mm (1/12 of an inch) across, clustered in branched racemes.^[3]^[4]

Origin of the name

Cultivation of this species, which is native to Southwest Asia (perhaps Persia) and which spread many centuries ago to western Europe, is very old, as is shown by the philological trace of its names in different Indo-European languages. These include the Persian word turehtezuk, the Greek kardamon, the Latin nasturtium and Arabic tuffa’ and hurf. In some languages there is a degree of confusion with watercress. It seems that the meaning of the word nasturtium (nasum torcere, because its smell causes the nose to turn up) must have been applied initially to garden cress, as both Pliny and Isidoro de Sevilla explain. The confusion remains with the terms used by the Hispano-Arabs. The word hurf is applied without distinction to watercress and garden cress (several species certainly of up to three different genera: Nasturtium, Lepidium and Cardaria). Thus the medieval agronomists of Andalusia went as far as differentiating between several hurf, such as hurf abyad, hurf babili, hurf madani….

Garden cress in agriculture

Garden cress is commercially grown in England, France, the Netherlands and Scandinavia.^[5]

Cultivation of garden cress is practical on both mass scales and on the individual scale. Garden cress is suitable for hydroponic cultivation and thrives in slightly alkaline water. In many local markets, the demand for hydroponically grown cress can exceed available supply, partially because cress leaves are not suitable for distribution in dried form, so can be only partially preserved. Consumers commonly acquire cress as seeds or (in Europe) from markets as boxes of young live shoots.^[5]

Edible shoots are typically harvested in one to two weeks after planting, when they are 5–13 cm (2 – 5 inches) tall.^[6]

Properties, uses and cultivation

Xenophon (400 _BC) mentions that the Persians used to eat this plant even before bread was known. It was also familiar to the Egyptians and was very much appreciated by the Greeks and Romans, who were very fond of banquets rich in spices and spicy salads. Columela (first century) makes direct reference to the cultivation of garden cress. In Los doce libros de Agricultura, he writes: ” …immediately after the calends of January, garden cress is sown out… when you have transplanted it before the calends of March, you will be able to harvest it like chives, but less often… it must not be cut after the calends of November because it dies from frosts, but can resist for two years if it is hoed and manured carefully… there are also many sites where it lives for up to ten years” (Book XI). The latter statements seem to indicate that he is also speaking of the perennial species L. Iatifolium, as L. sativum is an annual.

Almost all of the Andalusian agronomists of the Middle Ages (Ibn Hayyay, Ibn Wafid, Ibn al-Baytar, Ibn Luyun, Ibn al-Awwam) and many of the doctors, such as Maimonides, mention garden cress. Ibn al-Awwam also includes references from Abu al-Jair, Abu Abdalah as well as from Nabataean agriculture and, among other comments, he says: “Garden cress is sown between February and April (in January in Seville). It has small seeds which are mixed with earth for sowing to prevent the wind carrying them away…. It is harvested in May and is grown between ridges, in combination/conjunction with flax cultivation.”

Many of the authors of the old oriental and Mediterranean cultures emphasized the medicinal properties of cress, especially as an antiscorbutic, depurative and stimulant. Columela notes its vermifugal powers. Ibn al-Awwam refers to certain apparently antihistaminic properties, since it was used against insect bites and also as an insect repellent, in the form of a fumigant. It was perhaps Ibn al-Baytar, an Andalusian botanist (eighth century), who collected most information on its properties, summarizing the opinions of other authors such as El Farcy, who says that it incites coitus and stimulates the appetite; Ibn Massa, according to whom it dissipates colic and gets rid of tapeworms and other intestinal worms; or Ibn Massouih, who mentions that it eliminates viscous humours. Ibn al-Baytar also says that it is administered against leprosy, is useful for renal “cooling” and that, if hair is washed with garden cress water, it is “purified” and any loss is arrested.

In Iran and Morocco, the seeds are used as an aphrodisiac. In former Abyssinia, an edible oil was obtained from the seeds. In Eritrea, it was used as a dyestuff plant. Some Arab scholars have attributed garden cress’s reputation among Muslims to the fact that it was directly recommended by the Prophet.

Garden cress’s main use was always as an aromatic and slightly pungent plant. Not only in antiquity but also in the Middle Ages it enjoyed considerable prestige on royal tables. The young leaves were used for salads. The ancient Spartans ate them with bread. This use still continues and they are also eaten with bread and butter or with bread to which lemon, vinegar or sugar is added. However, it is mainly used nowadays in the seedling stage, the succulent hypocotyls being added to salads and as a garnish and decoration for dishes.

The roots, seeds and leaves have been used as a spicy condiment. Columela explains how oxygala, a type of curd cheese with herbs, was prepared: “Some people, after collecting cultivated or even wild garden cress, dry it in the shade and then, after removing the stem, add its leaves to brine, squeezing them and placing them in milk without any other seasoning, and adding the amount of salt they consider sufficient…. Others mix fresh leaves of cultivated cress with sweetened milk in a pot…”.

L. Iatifolium L. stands out for its horticultural interest; although it grows spontaneously on the edges of rivers and lakes, it is also occasionally grown in the same way as L. sativum. Its young leaves can be used for salads; the ancient Greeks and Romans used to grow it for this purpose. Its leaves and seeds were also used as a spicy condiment. Several sauces are prepared with its leaves, including in particular the bitter sauce of the paschal lamb of the Jews. The seeds of this species were known in England as the poor people’s pepper. The roots have been used on occasion as a substitute for radish.

In the fifteenth century, we know through Alonso de Herrera that garden cress was one of the vegetables most widely eaten in Castile. During the sixteenth century, obstinate attempts were made to introduce it into America. Right up to the beginning of the nineteenth century, its cultivation in Spain continued to be important, since Boutelou and Boutelou (1801) deal specifically with this crop in their Tratado de la huerta, commenting on the existence of several cultivars. At present, the cultivation of cress is very occasional in countries such as Spain and France. Water cress, in competition with garden cress, has eclipsed the cultivation of the latter. However, this is not the case in other central European countries or the United Kingdom, where its use is normal and the system of cultivation has changed substantially.

Botanical description

Cress is an annual, erect herbaceous plant, growing up to 50 cm. The basal leaves have long petioles and are lyrate-pinnatipartite; the caulinar leaves are laciniate-pinnate while the upper leaves are entire. The inflorescences are in dense racemes. The flowers have white or slightly pink petals, measuring 2 mm. The siliquae measure 5 to 6 x 4 mm, are elliptical, elate from the upper half, and glabrous. Cress flowers in the wild state between March and June.

It is an allogamous plant with self-compatible and self-incompatible forms and with various degrees of tolerance to prolonged autogamy. There are diploid forms, 2n = 2x = 16, and tetraploid forms, 2n = 4x =32. A degree of variability is noted in the character of the basal leaves which are cleft or split to a greater or lesser degree, a character which is controlled by a single incompletely dominant gene.

Ecology and phytogeography

Cress is a plant that is well suited to all soils and climates, although it does not tolerate frosts. In temperate conditions, it has a very rapid growth rate. It grows subspontaneously in areas transformed by humans, close to crops or human settlements. It appears in this way on the Iberian peninsula, mainly in the eastern regions.

Wild cress extends from the Sudan to the Himalayas. Most authors consider it to be a native of western Asia, whence it passed very quickly to Europe and the rest of Asia as a secondary crop, probably associated with cultivars of flax. Vavilov considers its main centre to be Ethiopia, where he found the widest variability; the Near East, central Asia and the Mediterranean are considered secondary centres. It is now naturalized in numerous parts of Europe, including the British Isles.

Cress in cookery

Genetic diversity

The genus Lepidium is made up of about 150 species, distributed throughout almost all temperate and subtropical regions of the world. On the Iberian peninsula and the Balearic Islands, at least 20 species or subspecies exist among the autochthonous and allochthonous taxa, some genetically close to L. sativum. Seven of them are exclusively endemic to the peninsula or, at the very most, are common with North Africa. Other close species are L. campestre (L.) R. Br. and L. ruderale L. which also have edible leaves. The leaves of L. campestre are used to prepare excellent sauces for fish.

Common cress (L. sativum L.), with regard to the anatomy of the leaf, stem and root, has been divided into three botanical varieties: vulgare, crispum and latifolium. The latter is the most mesomorphic, crispum the most xeromorphic and vulgare intermediate.

At present, most of the studies on the variability and development of new cultivars are being carried out in liaison with the VIR of St Petersburg, where there is a good collection of material. Of the 350 forms of garden cress studied in the Ukraine, Uzkolistnyti 3 was the best, being highly productive and of good quality. It is being used as the basis of improvement programmes, as it appreciably surpasses the best Soviet varieties in production and quality. Other cultivars well suited to European Russia are Tuikers Grootbladige (broad-leaved) and the lines Mestnyi k 137, k 106 and k 115. Of the types most cultivated in Europe, Early European, Eastern, Dagestan and Entire Leaved stand out, being distinguished by the length and shape of the leaf, earliness and susceptibility to cold. In Western Europe, one broad leaved type is especially appreciated (Broad Leaved French) as are curly types (Curly Leaved), the latter being used extensively to garnish dishes. In Africa, there are red, white and black varieties.

This crop is also arousing interest in Japan, and collecting expeditions to Nepal have been organized. Some specimens collected during an expedition to Iraq in 1986 are now stored in Abu Ghraib and in Gratersleben, Germany. There are also small collections of L. sativum in the PGRC in Addis Ababa (Ethiopia), at the ARARI of Izmir in Turkey and in Bari, Italy. At the Universidad Politécnica de Madrid there are accessions of 20 species of Lepidium, while the BGV of the Córdoba Botanical Garden keeps germplasm of the southern Iberian species of the genus.

Garden cress, raw
Nutritional value per 100 g (3.5 oz)
Energy	134 kJ (32 kcal)
Carbohydrates	5.5 g
– Sugars	4.4 g
– Dietary fiber	1.1 g
Protein	2.6 g
Vitamin A equiv.	346 μg (43%)
– beta-carotene	4150 μg (38%)
– lutein and zeaxanthin	12500 μg
Thiamine (vit. B₁)	0.08 mg (7%)
Riboflavin (vit. B₂)	0.26 mg (22%)
Niacin (vit. B₃)	1 mg (7%)
Pantothenic acid (B₅)	0.247 mg (5%)
Vitamin B₆	0.247 mg (19%)
Folate (vit. B₉)	80 μg (20%)
Vitamin C	69 mg (83%)
Vitamin E	0.7 mg (5%)
Vitamin K	541.9 μg (516%)
Calcium	81 mg (8%)
Iron	1.3 mg (10%)
Magnesium	38 mg (11%)
Manganese	0.553 mg (26%)
Phosphorus	76 mg (11%)
Potassium	606 mg (13%)
Link to USDA Database entry Percentages are roughly approximated using US recommendations for adults. Source: USDA Nutrient Database

Garden cress is added to soups, sandwiches and salads for its tangy flavor.^[6] It is also eaten as sprouts, and the fresh or dried seed pods can be used as a peppery seasoning (haloon).^[5] In England, cut cress shoots are commonly used in sandwiches with boiled eggs, mayonnaise and salt.

Garden cress can grow almost anywhere.

Nutrition profile

Garden cress is an important source of iron, folic acid, calcium, vitamins C, E and A. The seed contains arachidic and linoleic fatty acids. The seeds are high in calories and protein, whereas the leaves are an excellent source of vitamin A, C and folate.

Values for 100g of garden cress leaves
Energy	30 Kcal
Carbohydrates	5.5 g
Dietary fibre	1.1 g
Protein	2.6 g
Fat	0.7 g
Vitamin A	346 mcg
Folate	80 mcg
Vitamin C	69 mg
Calcium	81 mg
Iron	1.3 mg

Both the leaves and stems of cress can be eaten raw in salads or sandwiches, and are sometimes called cress sprouts. When buying cress, look for firm, evenly coloured, rich green leaves. Avoid cress with any signs of slime, wilting, or discoloration. If stored in plastic, it can last up to five days in a refrigerator. To prolong the life of cress, place the stems in a glass container with water and cover them, refrigerating the cress until it is needed.

Cultivation practices

Cress is an easily grown plant with few requirements. It can be broadcast after the winter frosts or throughout the year in temperate climates. However, Boutelou and Boutelou (1801) were already recommending sowing in shallow furrows, which enables surplus plants to be thinned out and facilitates hoeing. Sowing has to be repeated every 15 to 20 days so that there is no shortage of young shoots and new leaves for salads – the leaves of earlier sowings begin to get tough and are no longer usable. The seed sprouts four or six days after sowing, depending on the season, and the leaves are ready for consumption after two or three weeks.

The usual form of cultivation continues to be as described, with 15 to 20 cm between rows and the use of irrigation in the summer, since they are lightly rooted seedlings which can dry up in a few days. Its growth is very rapid and harvesting can begin in the same month as sowing, with yields reaching 6 tonnes per hectare.

Health benefits of garden cress

For women’s health

Emenagogue: Garden cress has mild oestrogenic properties. It helps to regulate the menstrual cycle.

Galactogogue: Kheer made of garden cress seeds increases milk production and secretion in lactating mothers. Because of its high iron and protein content, it is often given post-partum to lactating mothers.

Aphrodisiac: Garden cress helps to improve libido.

For the gastro intestinal tract

Garden cress helps purify blood and stimulate appetite. It is used during constipation as a laxative and a purgative. Paste made of the seeds can be taken internally with honey to treat amoebic dysentery. The mucilage of the germinating seeds allays the irritation of the intestines in dysentery and diarrhoea. Garden cress crushed and drunk with hot water is beneficial to treat colic especially in infants.

For the respiratory tract

Garden cress seeds are good expectorants and when chewed they treat sore throat, cough, asthma and headache. The aerial parts are used in the treatment of asthma and cough.

For anaemia

Garden cress seeds being the richest source of non-haeme iron [iron found in haemoglobin which is an easily absorbed dietary iron.] help to increase the haemoglobin levels. When taken regularly, it helps to alleviate anaemia. It is advisable to have vitamin C half an hour after consumption of these seeds as it enhances iron absorption.

For diabetes

The seed coat of germinating seeds contains mucilage, which has a phytochemical called lepidimoide. Studies show that seeds of the plant lower the glycemic response to a test meal.

note sodium 2-O-rhamnopyranosyl-4-deoxy-threo-hex-4-enopyranosiduronate (designated lepidimoide)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1075667/

ChemSpider 2D Image | epi-Lepidimoide | C12H17NaO10

epi-Lepidimoide

Sodium 6-deoxy-2-O-(4-deoxy-β-L-threo-hex-4-enopyranuronosyl)-α-L-glucopyranose

cas 145039-76-5 and 157676-09-0

The total synthesis of the unsaturated disaccharide, lepidimoide 4-deoxy--l-threo-hex-4-enopyranuronosyl-(1->2)-l-rhamnopyranose sodium salt, has been carried out from d-glucose and l-rhamnose (Tetrahedron Lett. 1993, 34, 2653), but the process is very long and complicated. A method for more easily producing this compound and in large quantities is necessary for further research. We have succeeded in conveniently synthesizing lepidimoide from okra (Hibiscus esculentus L.) fruit mucilage. At the same time, the isomer (epi-lepidimoide) was obtained as a byproduct. The structure was determined as the 4-deoxy--l-threo-hex-4-enopyranuronosyl-(1->2)-6-deoxy-l-glucopyranose sodium salt by spectral analysis. We found that lepidimoide easily epimerized to epi-lepidimoide in alkaline media. Both lepidimoide and epi-lepidimoide exhibited the same high activity in the cockscomb hypocotyls elongation test….Carbohydrate Research, Volume 339, Number 1, 2 January 2004 , pp. 9-19(11)

Dictionary of Natural Products, Supplement 3

books.google.co.in/books?isbn=0412604302

John Buckingham – 1996 – ‎Science

Lepidimoide. L-30020. 6-Deoxy-2-0-(4-deoxy-fi-L-lhreo-hex-4-enopyranuronosyl)-L- mannose, 9CI [157676-09-0] HOA—O …

lepidimoide

Sodium 2-O-L-rhamnopyranosyl-4-deoxy-alpha-L-threo-hex-4-eno-pyranosiduronate

Molecular Formula: C₁₂H₁₇NaO₁₀ Molecular Weight: 344.247149

sodium;(2S,3R,4S)-3,4-dihydroxy-2-[(2S,3R,4R,5R,6S)-2,4,5-trihydroxy-6-methyloxan-3-yl]oxy-3,4-dihydro-2H-pyran-6-carboxylate

Sodium2-O-L-rhamnopyranosyl-4-deoxy-α-L-threo-hex-4-eno-pyranosiduronate

For cancer

Garden cress seeds contain antioxidants like vitamin A and E which help protect cells from damage by free radicals. Hence, these seeds have a chemoprotective [drugs which protect healthy tissue from the toxic effects of anticancer drugs] nature.

Anti-Cancer:

Being a family of Brassica family it has good anti cancer property. Garden cress seeds contain antioxidants like vitamin A and E which help protect cells from damage by free radicals. Hence, these seeds have a chemo protective nature.

Few years back garden cress seeds/ halim/ aliv was not a common food item or a familiar to be heard. But as years passed it’s popularity and it’s importance have been realized and now people are aware of some of the facts of these seeds. Though these facts are also accompanied by some myths. So I chose to write and clear few myths and doubts of these seeds so that maximum people can make use of it in their lives and improve quality of their diet and nutrition.

Nutritive value of these seeds is very high. It is available in almost all parts of the world. Its high nutritive value and cheaper availability makes it possible for people of all the sections of society to include in the diet and increase nutritive value of their meals. Garden cress seeds are very high in Iron and Folic acid content. These seeds are use as herbal medicine to treat iron deficiency anemia. People consuming 2tsp/day have seen to have good increased levels of hemoglobin over a period of 1-2 months. Garden cress seeds also contains calcium, ascorbic acid, tocopherol, and beta-carotene which helps to improve body’s immunity.Garden Cress seeds are loaded with not just protein, but also linoleic and arachidic fatty acids. Since they contain phytochemicals that resemble estrogen to some extent, intake of these seeds helps to regulate menstruation and stimulate milk production in lactating mothers. That is why women are given foods containing Garden Cress following childbirth.

Traditionally garden cress seeds were considered to be useful only during last few weeks of gestation and post delivery. It is considered to be hot food. But the truth is that these seeds have ability too increase uterine contraction. So in later stages of pregnancy it helps in inducing labour but if in case consumed in early stage of pregnancy (1st trimester) it leads to spontaneous abortion. It is also very carefully prescribed to a hypothyroid patients because it belongs to cruciferous family and is a goitrogen that prevent iodine absorption.

How to eat:

1. Roasted slightly with added salt.

2. Soaked in water then added to milk or juice.

3. Chikki or laddoo can be made. (preparation similar to til laddoo/chikki).

How much to eat:

Start with 1 tsp/day and then an be taken 1 tsp/2c a day.

Cress seeds have many more medicinal properties and researches are still on to find its benefits on health. Garden cress should be eaten in moderation. Excess consumption of these seeds may hv adverse effect on health.

For other things

Garden cress seeds are memory boosters because they contain arachidic and linoleic acids. They help gaining lean body mass because they are a good source of iron and protein. Research has proved that 60 per cent women have hair loss due to low iron levels and poor protein. A teaspoon of garden cress seeds soaked in lime water helps in iron absorption, which in turn strengthens hair. The plant is also used in treating bleeding piles. The leaves are mildly stimulant and diuretic, useful in scorbutic [related to or resembling scurvy] diseases and liver complaints. A paste of the seeds with water is applied to chapped lips, and against sunburn.

Side-effects

It is an abortifacient [substance that induces abortion], if had in excess. It contains goitrogens that prevent iodine absorption in thyroids and hence can lead to hypothyroidism. If large quantities of garden cress are consumed, the mustard oil it contains may cause digestive difficulties in some people who are sensitive to it. Therefore, garden cress should be eaten in moderation.

Other uses

Garden cress, known as chandrashoor, and the seeds, known as halloon^[7] in India, are commonly used in the system of Ayurveda to prevent postnatal complications.^{[citation needed]}

Garden cress seeds, since ancient times, have been used in local traditional medicine of India.^[8] Garden cress seeds are bitter, thermogenic, depurative, rubefacient, galactogogue, tonic, aphrodisiac, ophthalmic, antiscorbutic, antihistaminic and diuretic. They are useful in the treatment ofasthma, coughs with expectoration, poultices for sprains, leprosy, skin disease, dysentery, diarrhoea, splenomegaly, dyspepsia, lumbago, leucorrhoea, scurvy and seminal weakness. Seeds have been shown to reduce the symptoms of asthma and improve lung function in asthmatics.^[9]The seeds have been reported as possessing a hypoglycemic property^[10] and the seed mucilage is used as a substitute for gum arabic and tragacanth.

Cress may be given to budgerigars.^[11] The seeds are employed as poultice for removing pain, swelling etc.Some use it in the belief that it can cure asthma, bronchitis bleeding piles.^[12]

Some use Lepidium sativum seeds for indigestion and constipation.^[13]

Prospects for improvement

Most of the genetic improvement work on garden cress is being carried out in the CIS, with little or no work being done at present in the countries of western Europe. Mainly early cultivars with a prolonged production period and better cold tolerance are being developed.

Cress can be grown and used like white mustard. It germinates more slowly at low temperatures, the emergence period being three or four days longer. Shortening this period is an interesting improvement objective.

However, cress’s recovery and its greater presence on markets mainly depends on a modification of cultivation and marketing techniques. In countries such as the United Kingdom, where this vegetable is normally to be found at the markets, cultivation takes place in greenhouses throughout the year. The whole succulent hypocotyls of the very young seedlings are eaten. The seed is placed on the soil surface on soft, level beds. It is finely sprinkled with water and then covered with sackcloth which has been steam-sterilized and moistened. The latter is frequently wetted to maintain moisture and is removed when the seedlings reach 4 to 5 cm in height (after approximately seven days in spring and autumn and ten days in winter). The yellowish leaves turn green after two to three days.

The cress is harvested when the first pair of cotyledon leaves have developed and it is marketed in small bags or trays, sometimes together with seedlings of white mustard.

Garden cress and white pepper are sometimes sown in the plastic trays or bags in which they will be sold, generally in peat with a nutrient solution.

References

Cassidy, Frederic Gomes and Hall, Joan Houston. Dictionary of American regional English, Harvard University Press, 2002. Page 97. ISBN 0-674-00884-7, ISBN 978-0-674-00884-7
Staub, Jack E, Buchert, Ellen. 75 Exceptional Herbs for Your Garden Published by Gibbs Smith, 2008. ISBN 1-4236-0251-X, 9781423602514
Vegetables of Canada. Published by NRC Research Press. ISBN 0-660-19503-8, ISBN 978-0-660-19503-2
Boswell, John T. and Sowerby, James. English Botany: Or, Coloured Figures of British Plants. Robert Hardwicke, 1863. Page 215.
Vegetables of Canada. NRC Research Press. ISBN 0-660-19503-8, ISBN 978-0-660-19503-2
Hirsch, David P.. The Moosewood Restaurant kitchen garden: creative gardening for the adventurous cook. Ten Speed Press, 2005. ISBN 1-58008-666-7, ISBN 978-1-58008-666-0
http://www.organicindia.com/PR_OH_chandrashoor.php
The Wealth of Indian Raw Materials ,. New Delhi: Publication and information Directorate. 1979. pp. CSIR Vol 9, Page 71–72.
NP, Archana; Anita, AM (2006). “A study on clinical efficacy of Lepidium sativum seeds in treatment of bronchial asthma”. Iran J Pharmacol Ther 5: 55–59.
M, Eddouks; Maghrani M, Zeggwagh NA, Michel JB (2005). “Study of the hypoglycaemic activity of Lepidium sativum L. aqueous extract in normal and diabetic rats”. J Ethnopharmacol 97: 391–395.
Budgerigars – Diets, PDSA.
Bhatiya, KN (1996). Modern Approach to Batany. India: Surya publications. p. 516.
Najeeb-Ur-Rehman, Mehmood MH, Alkharfy KM, Gilani AU, “Prokinetic and laxative activities of Lepidium sativum seed extract with species and tissue selective gut stimulatory actions. J Ethnopharmacol. 2011 Feb 2;

Time-lapse video showing garden cress growth

MARIZOMIB, Salinosporamide A

December 30, 2013 8:07 am / 1 Comment on MARIZOMIB, Salinosporamide A

MARIZOMIB
http://www.ama-assn.org/resources/doc/usan/marizomib.pdf
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-
cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-
2. (1R,4R,5S)-4-(2-chloroethyl)-1-{(S)-[(1S)-cyclohex-2-en-1-yl]hydroxymethyl}-5-methyl-
6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione

MOLECULAR FORMULA C15H20ClNO4
MOLECULAR WEIGHT 313.8

MANUFACTURER Nereus Pharmaceuticals, Inc.

NOTE….Nereus Pharmaceuticals was acquired by Triphase Research and Development in 2012.
CODE DESIGNATION NPI-0052
CAS REGISTRY NUMBER 437742-34-2

Scripps Institution of Oceanography (Originator)

US7183417

mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C.

[α]²³ _D−73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357);

FTIR (film) ν_max: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm⁻¹;

¹H NMR (CDCl₃, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);

¹³C NMR (CDCl₃, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00;

HRMS (ESI) calcd. for (M−H)⁻ C₁₅H₁₉ClNO₄312.1003, found 312.1003.

Marizomib, a highly potent proteasome inhibitor, is in early clinical development at Triphase Research and Development I Corp for the treatment of relapsed or relapsed/refractory multiple myeloma. Phase I clinical trials have also been carried out for the treatment of solid tumors and lymphoma; however, no recent developments have been reported for these studies.

HDAC inhibitors halt tumor cell differentiation and growth, and when combined with marizomib in preclinical in vitro and in vivo studies, show additive and synergistic antitumor activities.

The compound was discovered from a new marine-obligate gram-positive actinomycete (Salinispora tropica). Preclinical studies suggest that this next-generation compound may be superior to other proteasome inhibitors, with broader target inhibition, faster onset and longer duration of action, higher potency, and oral and intravenous availability. By inhibiting proteasomes, marizomib prevents the breakdown of proteins involved in signal transduction, which blocks growth and induces apoptosis in cancer cells.

In 2013, orphan drug designation was assigned in the U.S. for the treatment of multiple myeloma.

The compound was originally developed by Nereus Pharmaceuticals, which was acquired by Triphase Research and Development in 2012.

marizomib is a naturally-occurring salinosporamide, isolated from the marine actinomycete Salinospora tropica, with potential antineoplastic activity. Marizomib irreversibly binds to and inhibits the 20S catalytic core subunit of the proteasome by covalently modifying its active site threonine residues; inhibition of ubiquitin-proteasome mediated proteolysis results in an accumulation of poly-ubiquitinated proteins, which may result in the disruption of cellular processes, cell cycle arrest, the induction of apoptosis, and the inhibition of tumor growth and angiogenesis. This agent more may more potent and selective than the proteasome inhibitor bortezomib

Marizomib (NPI-0052) is an oral, irreversible ββ-lactone derivative that binds selectively to the active proteasomal sites. In vivo studies with marizomib demonstrate reduced tumor growth without significant toxicity in myeloma xenograft models. A phase I trial in refractory and relapsed MM is under way.

Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery.^[1]^[2] This novel marine natural product is produced by the recently described obligate marine bacteria Salinispora tropica and Salinispora arenicola, which are found in ocean sediment. Salinosporamide A belongs to a family of compounds, known collectively as salinosporamides, which possess a densely functionalized γ-lactam-β-lactone bicyclic core.

Salinosporamide A was discovered by William Fenical and Paul Jensen from Scripps Institution of Oceanography in La Jolla, CA. In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery.Salinospora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1. This compound also displayed potent and highly selective activity in the NCI’s 60-cell-line panel with a mean GI50 value (the concentration required to achieve 50% growth inhibition) of less than 10 nM and a greater than 4 log LC50 differential between resistant and susceptible cell lines. The greatest potency was observed against NCI-H226 non-small cell lung cancer, SF-539 CNS cancer, SK-MEL-28 melanoma, and MDA-MB-435 breast cancer (all with LC50 values less than 10 nM). Salinosporamide A was tested for its effects on proteasome function because of its structural relationship to omuralide. When tested against purified 20S proteasome, salinosporamide A inhibited proteasomal chymotrypsin-like proteolytic activity with an IC50 value of 1.3 nM.^[3] This compound is approximately 35 times more potent than omuralide which was tested as a positive control in the same assay. Thus, the unique functionalization of the core bicyclic ring structure of salinosporamide A appears to have resulted in a molecule that is a significantly more potent proteasome inhibitor than omuralide.^[1]

Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.

Biosynthesis

Salinosporamide A and B building blocks

Proposed biosynthesis of the nonproteinogenic amino-acid beta-hydroxycyclohex-2′-enylanine (3) (R = H or S~PCP) via a shunt in the phenylalanine biosynthetic pathway

Biosynthesis

It was originally hypothesized that salinosporamide B was a biosynthetic precursor to salinosporamide A due to their structural similarities.

It was thought that the halogenation of the unactivated methyl group was catalyzed by a non-heme iron halogenase.^[4]^[5]Recent work using ¹³C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.^[4]^[6]

While they share the biosynthetic precursors acetate and presumed β-hydroxycyclohex-2′-enylalanine (3), they differ in the origin of the four-carbon building block that gives rise to their structural differences involving the halogen atom. A hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway is most likely the biosynthetic mechanism in which acetyl-CoA and butyrate-derived ethylmalonyl-CoA condense to yield the β-ketothioester (4), which then reacts with (3) to generate the linear precursor (5).

The first stereoselective synthesis was reported by Rajender Reddy Leleti and E. J.Corey.^[7] Later several routes to the total synthesis of salinosporamide A have been reported.^[7]^[8]^[9]^[10]

In vitro studies using purified 20S proteasomes showed that salinosporamide A has lower EC50 for trypsin-like (T-L) activity than does Bortezomib. In vivo animal model studies show marked inhibition of T-L activity in response to salinosporamide A, whereas bortezomib enhances T-L proteasome activity.

Initial results from early-stage clinical trials of salinosporamide A in relapsed/refractory multiple myeloma patients were presented at the 2011 American Society of Hematology annual meeting.^[11] Further early-stage trials of the drug in a number of different cancers are ongoing.^[12]

Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003). “Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora”. Angew. Chem. Int. Ed. Engl. 42 (3): 355–7.doi:10.1002/anie.200390115. PMID 12548698.
Chauhan D, Catley L, Li G et al. (2005). “A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib”. Cancer Cell 8 (5): 407–19.doi:10.1016/j.ccr.2005.10.013. PMID 16286248.
K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
Beer LL, Moore BS (2007). “Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica”. Org. Lett. 9 (5): 845–8.doi:10.1021/ol063102o. PMID 17274624.
Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT (2006). “Nature’s inventory of halogenation catalysts: oxidative strategies predominate”. Chem. Rev.106 (8): 3364–78. doi:10.1021/cr050313i.PMID 16895332.
Tsueng G, McArthur KA, Potts BC, Lam KS (2007). “Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins”. Applied Microbiology and Biotechnology 75 (5): 999–1005. doi:10.1007/s00253-007-0899-7.PMID 17340108.
Reddy LR, Saravanan P, Corey EJ (2004). “A simple stereocontrolled synthesis of salinosporamide A”. J. Am. Chem. Soc. 126 (20): 6230–1. doi:10.1021/ja048613p.PMID 15149210.
Ling T, Macherla VR, Manam RR, McArthur KA, Potts BC (2007). “Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052)”.Org. Lett. 9 (12): 2289–92. doi:10.1021/ol0706051. PMID 17497868.
Ma G, Nguyen H, Romo D (2007). “Concise Total Synthesis of (±)-Salinosporamide A, (±)-Cinnabaramide A, and Derivatives via a Bis-Cyclization Process: Implications for a Biosynthetic Pathway?”. Org. Lett. 9 (11): 2143–6. doi:10.1021/ol070616u. PMC 2518687.PMID 17477539.
Endo A, Danishefsky SJ (2005). “Total synthesis of salinosporamide A”. J. Am. Chem. Soc. 127 (23): 8298–9.doi:10.1021/ja0522783. PMID 15941259.
“Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011)”. The Myeloma Beacon. 2012-01-23. Retrieved 2012-06-10.
ClinicalTrials.gov: Marizomib

……………………………………………………

IMPORTANT PAPERS

Total synthesis of salinosporamide A
Org Lett 2008, 10(19): 4239

Entry to heterocycles based on indium-catalyzed conia-ene reactions: Asymmetric synthesis of (-)-salinosporamide A
Angew Chem Int Ed 2008, 47(33): 6244

A concise and straightforward total synthesis of (+/-)-salinosporamide A, based on a biosynthesis model
Org Biomol Chem 2008, 6(15): 2782

Formal synthesis of salinosporamide A starting from D-glucose
Synthesis (Stuttgart) 2009, 2009(17): 2983

Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A
Tetrahedron 2012, 68(32): 6504

………………

Salinosporamide A(1) was recently discovered by Fenical et al. as a bioactive product of a marine microorganism that is widely distributed in ocean sediments. Feeling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W., Angew. Chem. Int. Ed., 2003, 42, 355–357.

Structurally Salinosporamide A closely resembles the terrestrial microbial product omuralide (2a) that was synthesized by Corey et al. several years ago and demonstrated to be a potent inhibitor of proteasome function. See, (a) Corey, E. J.; Li, W. D., Z. Chem. Pharm. Bull., 1999, 47, 1–10; (b) Corey, E. J., Reichard, G. A.; Kania, R., Tetrahedron Lett., 1993, 34, 6977–6980; (c) Corey, E. J.; Reichard, G. A., J. Am. Chem. Soc., 1992, 114, 10677–10678; (d) Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.; Schreiber, S. L., Proc. Natl. Acad. Sci. USA, 1994, 91, 3358–3362.

Omuralide is generated by β-lactonization of the N-acetylcysteine thiolester lactacystin (2b) that was first isolated by the Omura group as a result of microbial screening for nerve growth factor-like activity. See, Omura, S., Fujimoto, T., Otoguro, K., Matsuzaki, K., Moriguchi, R., Tanaka, H., Sasaki, Y., Antibiot., 1991, 44, 113–116; Omura, S., Matsuzaki, K., Fujimoto, T., Kosuge, K., Furuya, T., Fujita, S., Nakagawa, A., J. Antibiot., 1991, 44, 117–118.

Salinosporamide A, the first compound Fenical’s group isolated from Salinospora, not only had a never-before-seen chemical structure 1, but is also a highly selective and potent inhibitor of cancer-cell growth. The compound is an even more effective proteasome inhibitor than omuralide and, in addition, it displays surprisingly high in vitro cytotoxic activity against many tumor cell lines (IC₅₀values of 10 nM or less). Fenical et al. first found the microbe, which they’ve dubbed Salinospora, off the coasts of the Bahamas and in the Red Sea. See,Appl. Environ. Microbiol., 68, 5005 (2002).

Fenical et al. have shown that Salinospora species requires a salt environment to live. Salinospora thrives in hostile ocean-bottom conditions: no light, low temperature, and high pressure. The Fenical group has now identified Salinosporain five oceans, and with 10,000 organisms per cm³of sediment and several distinct strains in each sample; and according to press reports, they’ve been able to isolate 5,000 strains. See, Chemical & Engineering News, 81, 37 (2003).

A great percentage of the cultures Fenical et al. have tested are said to have shown both anticancer and antibiotic activity. Like omuralide 2a, salinosporamide A inhibits the proteasome, an intracellular enzyme complex that destroys proteins the cell no longer needs. Without the proteasome, proteins would build up and clog cellular machinery. Fast-growing cancer cells make especially heavy use of the proteasome, so thwarting its action is a compelling drug strategy. See, Fenical et al., U.S. Patent Publication No. 2003-0157695A1

PATENTS

WO 2005113558

http://www.google.com/patents/US7183417

Part I. Synthesis of the Salinosporamide A(1)

EXAMPLE 1

(4S, 5R) Methyl 4,5-dihydro-2 (4-methoxyphenyl)-5-methyloxazole-4-carboxylate (4)

A mixture of (2S, 3R)-methyl 2-(4-methoxybenzamido)-3-hydroxybutanoate (3) (35.0 g, 131 mmol) and p-TsOH.H₂O (2.5 g, 13.1 mmol) in toluene (400 mL) was heated at reflux for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, brine and dried over Na₂SO₄. The solvent was removed in vacuo to give crude oxazoline as yellow oil. Flash column chromatography on silica gel (eluent 15% EtOAc-Hexanes) afforded the pure oxazoline (26.1 g, 80%) as solid.

R_f=0.51 (50% ethyl acetate in hexanes), mp, 86–87° C.; [α]²³ _D+69.4 (c 2.0, CHCl₃); FTIR (film) ν_max: 2955, 1750, 1545, 1355, 1187, 1011, 810 cm⁻¹; ¹HNMR(CDCl₃, 400 MHz): δ 7.87 (2H, d, J=9.2 Hz), 6.84 (2H, d, J=8.8 Hz), 4.90 (1H, m), 4.40 (1H, d, J=7.6 Hz), 3.79 (3H,s), 3.71 (3H, s), 1.49 (3H, d, J=6.0 Hz); ¹³C NMR (CDCl₃, 100 MHz): δ 171.93, 165.54, 162.64, 130.52, 119.80, 113.85, 78.91, 75.16, 55.51, 52.73, 21.14; HRMS (ESI) calcd for C₁₃H₁₆NO₄(M+H)⁺.250.1079, found 250.1084.

EXAMPLE 2

(4R, 5R)-Methyl 4-{(benzyloxy) methyl)}-4,5-dihydro-2-(4-methoxyphenyl)-5-methyloxazole-4-carboxylate (5)

To a solution of LDA (50 mmol, 1.0 M stock solution in THF) was added HMPA (24 mL, 215 mmol) at −78° C. and then oxazoline 4 (12.45 g, 50 mmol, in 20 mL THF) was added dropwise with stirring at −78° C. for 1 h to allow complete enolate formation. Benzyloxy chloromethyl ether (8.35 mL, 60 mmol) was added at this temperature and after stirring the mixture at −78° C. for 4 h, it was quenched with water (50 mL) and warmed to 23° C. for 30 min. Then the mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:4 then 1:3) to give the benzyl ether 5 (12.7 g, 69%).

R_f=0.59 (50% ethyl acetate in hexanes). [α]²³ _D−6.3 (c 1.0, CHCl₃); FTIR (film) (ν_max; 3050, 2975, 1724, 1642, 1607, 1252, 1027, 745, 697 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 7.96 (2H, d, J=9.2 Hz), 7.26 (5H, m), 6.90 (2H, J=8.8 Hz), 4.80 (1H, m), 4.61 (2H, s), 3.87 (3H, m), 3.81 (3H, s), 3.73 (3H, s), 1.34 (3H, d, J=6.8 Hz); ¹³C NMR (CDCl₃, 100 MHZ): 6171.23, 165.47, 162.63, 138.25, 130.64, 128.52, 127.87, 127.77, 120.15, 113.87, 81.40, 79.92, 73.91, 73.43, 55.58, 52.45, 16.92; HRMS (ESI) calcd for C₂₁H₂₄O₅(M+H)⁺370.1654, found 370.1644.

EXAMPLE 3

(2R,3R)-Methyl 2-(4-methoxybenzylamino)-2-((benzyloxy)methyl)-3hydroxybutanoate (6)

To a solution of oxazoline 5 (18.45 g, 50 mmol) in AcOH (25 mL) at 23° C. was added in portions NaCNBH₃(9.3 g, 150 mmol). The reaction mixture was then stirred at 40° C. for 12 h to allow complete consumption of the starting material. The reaction mixture was diluted with water (100 mL), neutralized with solid Na₂CO₃and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over NaSO₄and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give the N-PMB amino alcohol 6 (16.78 g, 90%).

R_f=0.50 (50% ethyl acetate in hexanes). [α]²³ _D−9.1(c 1.0, CHCl₃); FTIR (film) ν_max; 3354, 2949, 1731, 1511, 1242, 1070, 1030, 820, 736, 697 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 7.32 (7H, m), 6.87 (2H, d, J=8.8 Hz), 4.55 (2H, m), 4.10 (1H, q, J=6.4 Hz), 3.85 (2H, dd, J=17.2, 10.0 Hz), 3.81 (3H, s,), 3.77 (3H, s), 3. 69 (2H, dd, J=22.8, 11.6 Hz), 3.22 (2H, bs), 1.16 (3H, d, J=6.0 Hz); ¹³C NMR (CDCl₃, 100 MHz): δ 173.34, 159.03, 137.92, 132.51, 129.78, 128.67, 128.07, 127.98, 114.07, 73.80, 70.55, 69.82, 69.65, 55.51, 55.29, 47.68, 18.15; HRMS (ESI) calcd. for C₂₁H₂₈NO₅(M+H)⁺374.1967, found 374.1974.

EXAMPLE 4

(2R,3R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-hydroxybutanoate (7)

A solution of amino alcohol 6 (26.2 g, 68.5 mmol) in Et₂O (200 mL) was treated with Et₃N (14.2 mL, 102.8 mmol) and trimethylchlorosilane (10.4 mL, 82.2 mmol) at 23° C. and stirred for 12 h. After completion, the reaction mixture was diluted with ether (200 mL) and then resulting suspension was filtered through celite. The solvent was removed to furnish the crude product (31.2 g, 99%) in quantitative yield as viscous oil. A solution of this crude trimethylsilyl ether (31.1 g) in CH₂Cl₂(200 mL) was charged with diisopropylethylamine (14.2 mL, 81.6 mmol) and then cooled to 0° C. Acryloyl chloride (6.64 mL, 82.2 mmol) was added dropwise with vigorous stirring and the reaction temperature was maintained at 0° C. until completion (1 h). The reaction mixture was then diluted with CH₂Cl₂(100 mL) and the organic layer was washed with water and brine. The organic layer was separated and dried over Na₂SO₄. The solvent was removed to afford the crude acrylamide 7 as a viscous oil. The crude product was then dissolved in Et₂O (200 mL) and stirred with 6N HCl (40 mL) at 23° C. for 1 h. The reaction mixture was diluted with water (100 mL) and concentrated to provide crude product. The residue was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:1) to give pure amide 7 (28.3 g, 96%) as colorless solid, mp 88–89° C.

R_f=0.40 (50% ethyl acetate in hexanes), [α]²³ _D−31.1 (c 0.45, CHCl₃), FTIR (film) ν_max; 3435, 2990, 1725, 1649, 1610, 1512, 1415, 1287, 1242, 1175, 1087, 1029, 732, 698 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.25 (5H, m), 7.15 (2H, d, J=6.0 Hz), 6.85 (2H, d, J=7.5 Hz), 6.38 (2H, d, J=6.0 Hz), 5.55 (1H, t, J=6.0 Hz), 4.81 (2H, s), 4.71 (1H, q, J=6.5 Hz), 4.35 (2H, s), 4.00 (1H, d, J=10.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.76 (3H, s), 3.75 (3H, s), 3.28 (1H, bs), 1.22 (3H, d, J=6.0 Hz); ¹³C NMR (CDCl₃, 125 MHz): δ 171.87, 168.74, 158.81, 137.73, 131.04, 129.68, 128.58, 128.51, 127.94, 127.72, 127.20, 127.14, 114.21, 73.71, 70.42, 69.76, 67.65, 55.45, 52.52, 49.09, 18.88; HRMS (ESI) calcd. for C₂₄H₃₀NO₆(M+H)⁺428.2073, found 428.2073.

EXAMPLE 5

(R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-oxybutanoate (8)

To a solution of amide 7 (10.67 g, 25.0 mmol) in CH₂Cl₂(100 mL) was added Dess-Martin periodinane reagent (12.75 g, 30.0 mmol, Aldrich Co.) at 23° C. After stirring for 1 h, the reaction mixture was quenched with aq NaHCO₃—Na₂S₂O₃(1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude ketone. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes) to give pure keto amide 8 (10.2 g, 96%).

R_f=0.80 (50% ethyl acetate in hexanes), mp 85 to 86° C.; [α]²³ _D−12.8 (c 1.45, CHCl₃); FTIR (film) ν_max: 3030, 2995, 1733, 1717, 1510, 1256, 1178, 1088, 1027, 733, 697 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.30 (2H, d, J=8.0), 7.25 (3H, m), 7.11 (2H, m), 6.88 (2H, d, J=9.0 Hz), 6.38 (2H, m), 5.63 (1H, dd, J=8.5, 3.5 Hz), 4.93 (1H, d, J=18.5 Hz), 4.78 (1H, d, J=18.5, Hz), 4.27 (2H, m), 3.78 (3H, s), 3.76 (3H, s), 2.42 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 198.12, 169.23, 168.62, 158.01, 136.95, 130.64, 130.38, 128.63, 128.13, 127.77, 127.32, 114.33, 77.49, 73.97, 70.66, 55.49, 53.09, 49.03, 28.24; HRMS (ESI) calcd. for C₂₄H₂₈NO₆(M+H)⁺ 426.1916, found 426.1909.

EXAMPLE 6

(2R,3S)-Methyl-1-(4-methoxybenzyl)-2-((benzyloxy)methyl)-3-hydroxy-3-methyl-4-methylene-5-oxopyrrolidine-2-carboxylate (9+10)

A mixture of keto amide 8 (8.5 g, 20.0 mmol) and quinuclidine (2.22 g, 20.0 mmol) in DME (10 mL) was stirred for 5 h at 23° C. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) washed with 2N HCl, followed by water and dried over Na₂SO₄. The solvent was removed in vacuo to give the crude adduct (8.03 g, 94.5%, 3:1 ratio of 9 to 10 dr) as a viscous oil. The diastereomeric mixture was separated at the next step, although small amounts of 9 and 10 were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2) for analytical purposes.

Major Diastereomer (9).

[α]²³ _D−37.8 (c 0.51, CHCl₃); FTIR (film) v_max: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808,734 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.29 (5H, m), 7.15 (2H, d, J=7.5 Hz), 6.74 (2H, d, J=8.5 Hz), 6.13 (1H, s), 5.57 (1H, s), 4.81 (1H, d, J=14.5 Hz), 4.45(1H, d, J=15.0 Hz), 4.20 (1H, d, J=12.0 Hz), 4.10 (1H, d, J=12.0 Hz) 3.75 (3H, s), 3.70 (1H, d, J=10.5 Hz), 3.64 (3H, s), 3.54 (1H, d, J=10.5 Hz), 2.55 (1H, bs, OH), 1.50 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 169.67, 168.42, 158.97, 145.96, 137.57, 130.19, 130.12, 128.53, 127.83, 127.44, 116.79, 113.71, 76.32, 76.00, 73.16, 68.29, 55.45, 52.63, 45.36, 22.64; HRMS (ESI) calcd. for C₂₄H₂₈NO₆(M+H)⁺ 426.1916, found 426.1915.
Minor Diastereomer (10).
[α]²³ _D−.50.1 (c 0.40, CHCl₃); FTIR (film) ν_max: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808, 734 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.29 (5H, m), 7.12 (2H, d, J=7.5 Hz), 6.73 (2H, d, J=8.5 Hz), 6.12 (1H, s), 5.57 (1H, s), 4.88 (1H, d, J=15.5 Hz), 4.31 (1H, d, J=15.0 Hz), 4.08 (3H, m), 3.99 (1H, d, J=12.0 Hz) 3.73 (3H, s), 3.62 (3H, s), 3.47 (1H, bs, OH), 3.43 (1H, d, J=10.0 Hz), 1.31 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 169.65, 167.89, 159.13, 147.19, 136.95, 130.29, 129.76, 128.74, 128.19, 127.55, 116.80, 113.82, 76.21, 75.66, 73.27, 68.02, 55.45, 52.52, 45.24, 25.25; HRMS (ESI) calcd. for (M+H)⁺ C₂₄H₂₈NO₆426.1916, found 426.1915.

EXAMPLE 7

Silylation of 9 and 10 and Purification of 11.

To a solution of lactams 9 and 10 (7.67 g, 18 mmol) in CH₂Cl₂(25 ml) was added Et₃N (7.54 ml, 54 mmol), and DMAP (2.2 g, 18 mmol) at 0° C., and then bromomethyl-dimethylchlorosilane (5.05 g, 27 mmol) (added dropwise). After stirring the mixture for 30 min at 0° C., it was quenched with aq NaHCO₃and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine and dried over Na₂SO₄. The solvent was removed in vacuo to give a mixture of the silated derivatives of 9 and 10 (9.83 g, 95%). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:4) to give pure diastereomer 11 (7.4 g, 72%) and its diastereomer (2.4 g, 22%).

Silyl Ether (11).

R_f=0.80 (30% ethyl acetate in hexanes). [α]²³ _D−58.9 (c 0.55, CHCl₃); FTIR (film) ν_max; 3050, 2995, 1738, 1697, 1512, 1405, 1243, 1108, 1003, 809, 732 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.27 (5H, m), 7.05 (2H, d, J=7.0 Hz), 6.71 (2H, d, J=8.5 Hz), 6.18 (1H, s), 5.53 (1H, s), 4.95 (1H, d, J=15.5 Hz), 4.45 (1H, d, J=15.0 Hz), 4.02 (1H, J=12.0 Hz), 3.86 (1H, d, J=11.5 Hz) 3.72 (3H, s), 3.68 (3H, s), 3.65 (1H, d, J=10.5 Hz), 3.30 (1H, d, J=10.0 Hz), 2.34 (2H, d, J=2.0 Hz), 1.58 (3H, s), 0.19 (3H, s), 0.18 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 168.62, 168.12, 158.93, 145.24, 137.53, 130.32, 130.30, 128.49, 127.76,127.22, 117.26, 113.60, 78.55, 78.03, 72.89, 68.45, 55.43, 52.37, 45.74, 21.87, 17.32, −0.72, −0.80; HRMS (ESI) Calcd. for C₂₇H₃₅BrNO₆Si (M+H)⁺576.1417, found 576.1407.

EXAMPLE 8

Conversion of (11) to (12).

To a solution of compound 11 (5.67 g 10 mmol) in benzene (250 mL) at 80° C. under nitrogen was added a mixture of tributyltin hydride (4.03 ml, 15 mmol) and AIBN (164 mg, 1 mmol) in 50 ml benzene by syringe pump over 4 h. After the addition was complete, the reaction mixture was stirred for an additional 4 h at 80° C. and the solvent was removed in vacuo. The residue was dissolved in hexanes (20 mL) and washed with saturated NaHCO₃(3×25 mL), water and dried over Na₂SO₄. The solvent was removed in vacuo to give crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to afford the pure 12 (4.42 g, 89%).

R_f=0.80 (30% ethyl acetate in hexanes). [α]²³ _D−38.8 (c 0.25, CHCl₃); FTIR (film) ν_max; 3025, 2985, 1756, 1692, 1513, 1247, 1177, 1059, 667 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.28 (5H, m), 7.09 (2H, d, J=7.0 Hz), 6.73 (2H, d, J=9.0 Hz), 4.96(1H, d, J=15.0 Hz), 4.35 (1H, d, J=15.5 Hz), 3.97 (1H, d, J=12.5 Hz), 3.86 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.72 (3H, s), 3.65 (3H, s), 3.27 (1H, d, J=10.5 Hz), 2.67 (1H, t, J=4.0 Hz), 2.41 (1H, m), 1.79 (1H, m), 1.46 (3H, s), 0.77 (1H, m), 0.46 (1H, m), 0.10 (3H, s), 0.19 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 175.48, 169.46, 158.76, 137.59, 131.04, 129.90, 128.58, 127.88, 127.52, 113.59, 113.60, 81.05, 78.88, 73.12, 69.03, 55.45, 51.94, 48.81, 45.50, 22.79, 17.06, 7.76, 0.54; HRMS (ESI) calcd. for (M+H)⁺ C₂₇H₃₆NO₆Si 498.2312, found 498.2309.

EXAMPLE 9

Debenzylation of (12).

A solution of 12 (3.98 g, 8 mmol) in EtOH (50 ml) at 23° C. was treated with 10% Pd—C (˜1 g) under an argon atmosphere. The reaction mixture was evacuated and flushed with H₂gas (four times) and then stirred vigorously under an atmosphere of H₂(1 atm, H₂balloon) at 23° C. After 12 h, the reaction mixture was filtered through Celite and concentrated in vacuo to give the crude debenzylation product (3.08 g, 95%) which was used for the next step. A small amount crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:3) for analytical purposes. R_f=0.41 (50% ethyl acetate in hexanes).

mp, 45–47° C.; [α]²³ _D−30.9 (c 0.55, CHCl₃); FTIR (film) ν_max: 3432, 3020, 2926, 1735, 1692, 1512, 1244, 1174, 1094, 1024, 870, 795 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 7.36 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.16 (1H, d, J=15.0 Hz), 4.29 (1H, d, J=15.0 Hz), 3.92 (1H, m), 3.78 (3H, s), 3.68 (3H, s), 3.45 (1H, m), 2.53 (1H, t, J=4.0 Hz), 2.42 (1H, m), 1.82 (1H, m), 1.50 (3H, s), 1.28 (1H, m), 0.75 (1H, m), 0.47 (1H, m), 0.11 (3H, s), 0.02 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 175.82, 169.51, 159.32, 131.00, 129.72, 114.52, 80.79, 80.13, 61.85, 55.48, 51.99, 49.29, 45.06, 23.11, 17.03, 7.44, 0.54; HRMS (ESI) calcd. for C₂₀H₃₀NO₆Si (M+H)⁺ 408.1842, found 408.1846.

EXAMPLE 10

Oxidation to Form Aldehyde (13).

To a solution of the above alcohol from debenzylation of 12 (2.84 g, 7 mmol) in CH₂Cl₂(30 mL) was added Dess-Martin reagent (3.57 g, 8.4 mmol) at 23° C. After stirring for 1 h at 23° C., the reaction mixture was quenched with aq NaHCO₃—Na₂S₂O₃(1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude aldehyde. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give pure aldehyde 13 (2.68 g, 95%). R_f=0.56 (50% ethyl acetate in hexanes).

mp, 54–56° C.; [α]²³ _D−16.5 (c 0.60, CHCl₃); FTIR (film) ν_max: 3015, 2925, 1702 1297, 1247, 1170, 1096, 987, 794 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 9.62 (1H, s), 7.07 (2H, d, J=8.0 Hz), 6.73 (2H, d, J=8.5 Hz), 4.49 (1H, quart, J=8.5 Hz), 3.70 (3H, s), 3.67 (3H, s), 2.36 (2H, m), 1.75 (1H, m), 1.37 (3H, s), 0.73 (1H, m), 0.48 (1H, m), 0.07 (3H, s), 0.004 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 197.26, 174.70, 167.36, 158.07, 130.49, 128.96, 113.81, 83.97, 82.36, 55.34, 52.43, 47.74, 46.32, 23.83, 16.90, 7.52, 0.56, 0.45; HRMS (ESD calcd. for C₂₀H₂₈NO₆Si (M+H)⁺ 406.1686, found 406.1692.

EXAMPLE 11

Conversion of (13) to (14).

To a solution of freshly prepared cyclohexenyl zinc chloride (10 mL, 0.5 M solution in THF, 5 mmol) (see Example 15 below) at −78° C. under nitrogen was added a −78° C. solution of aldehyde 13 (1.01 g, in 3 ml of THF, 2.5 mmol). After stirring for 5 h at −78° C. reaction mixture was quenched with water (10 mL) then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na₂SO₄and solvent was removed in vacuo to give crude product (20:1 dr). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2 affords the pure major diastereomer 14 (1.0 g, 83%) and a minor diastereomer (50 mg 5%). For 14: R_f=0.56 (50% ethyl acetate in hexanes).

mp, 79–81° C.; [a]²³ _D−28.5 (c 1.45, CHCl₃); FTIR (film) ν_max: 3267, 2927, 2894, 2829, 1742, 1667, 1509, 1248, 1164, 1024, 795 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.34 (2H, d, J=8.5 Hz), 6.81 (2H, d, J=9.0 Hz), 5.84 (1H, m), 5.73 (1H, m), 4.88 (1H, d, J=15.5 Hz), 4.39 (1H, d, J=14.5 Hz), 4.11 (1H, t, J=6.5 Hz), 3.77 (3H, s), 3.58 (3H, s), 3.00 (1H, m), 2.95 (1H, d, J=9.0 Hz), 2.83 (1H, t, J=3.5 Hz), 3.36 (1H, m), 2.27 (1H, m), 1.98 (2H, m), 1.74 (3H, m), 1.62 (3H, s), 1.14 (2H, m), 0.59 (1H, m), 0.39 (11H, m), 0.13 (3H, s), 0.03 (3H, s); ¹³C NMR (CDCl₃, 125 MHz): δ 176.80, 170.03, 158.27, 131.86, 131.34, 128.50, 126.15, 113.40, 83.96, 82.45, 77.17, 55.45, 51.46, 48.34, 48.29, 39.08, 28.34, 25.29, 22.45, 21.09, 17.30, 7.75, 0.39, 0.28; HRMS (ESI) calcd. for C₂₆H₃₈NO₆Si (M+H)⁺ 488.2468, found 488.2477.

EXAMPLE 12

Tamao-Fleming Oxidation of (14) to (15).

To a solution of 14 (0.974 g, 2 mmol) in THF (5 mL) and MeOH (5 mL) at 23° C. was added KHCO₃(0.8 g, 8 mmol) and KF (0.348 g, 6 mmol). Hydrogen peroxide (30% in water, 5 mL) was then introduced to this mixture. The reaction mixture was vigorously stirred at 23° C. and additional hydrogen peroxide (2 ml) was added after 12 h. After 18 h, the reaction mixture was quenched carefully with NaHSO₃solution (15 mL). The mixture was extracted with ethyl acetate (3×25 mL) and the combined organic layers were washed with water and dried over Na₂SO₄. The solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate) to give the pure triol 15 (0.82 g, 92%).

R_f=0.15 (in ethyl acetate). mp, 83–84° C.; [α]²³ _D: +5.2 (c 0.60, CHCl₃); FTIR (film) ν_max; 3317, 2920, 2827, 1741, 1654, 1502, 1246, 1170, 1018, 802 cm⁻¹; ¹HNMR(CDCl₃, 500 MHz): δ 7.77 (2H, d, J=8.0 Hz), 6.28 (2H, d, J=8.0 Hz), 5. 76 (1H, m), 5.63 (1H, d, J=10.0 Hz), 4.74 (1H, d, J=15.5 Hz), 4.54 (1H, d, J=15.0 Hz), 4.12 (1H, d, J=2.5 Hz), 3.80 (1H, m), 3.76 (3H, s), 3.72 (1H, m), 3.68 (3H, s), 3.00 (1H, m), 2.60 (1H, br), 2.20 (1H, m), 1.98 (2H, s), 1.87 (1H, m), 1.80 (1H, m), 1.71 (2H, m), 1.61 (3H, s), 1.14 (2H, m); ¹³C NMR (CDCl₃, 125 MHz): δ 178.99, 170.12, 158.27, 131.30, 130.55, 128.13, 126.39, 113.74, 81.93, 80.75, 76.87, 61.61, 55.45, 51.97, 51.32, 48.07, 39.17, 27.71, 27.13, 25.22, 21.35, 21.22; HRMS (ESI) calcd. for C₂₄H₃₄NO₇(M+H)⁺ 448.2335, found 448.2334.

EXAMPLE 13

Deprotection of (15) to (16).

To a solution of 15 (0.670 g, 1.5 mmol) in acetonitrile (8 mL) at 0° C. was added a pre-cooled solution of ceric ammonium nitrate (CAN) (2.46 g 4.5 mmol in 2 mL H₂O). After stirring for 1 h at 0° C. the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaCl solution (5 mL) and organic layers was dried over Na₂SO₄. The solvent was removed in vacuo to give the crude product which was purified by column chromatography (silica gel, ethyl acetate) to give the pure 16 (0.4 g, 83%).

R_f=0.10 (5% MeOH in ethyl acetate). mp, 138 to 140° C.; [α]²³ _D+14.5 (c 1.05, CHCl₃); FTIR (film) ν_max3301, 2949, 2911, 2850, 1723, 1673, 1437, 1371, 1239, 1156, 1008, 689 cm⁻¹; ¹H NMR (CDCl₃, 600 MHz): δ 8.48 (1H, br), 6.08 (1H, m), 5. 75 (1H, d, J=9.6 Hz), 5.29 (1H, br), 4.13 (1H, d, J=6.6 Hz), 3.83 (3H, m), 3.79 (1H, m), 3.72 (1H, m), 2.84 (1H, d, J=10.2 Hz), 2.20 (1H, m), 2.16 (1H, br), 1.98 (3H, m), 1.77 (3H, m), 1.59 (1H, m), 1.54 (3H, s), 1.25 (1H, m). ¹³C NMR (CDCl₃, 125 MHz): δ 180.84, 172.95, 135.27, 123.75, 82.00, 80.11, 75.56, 62.39, 53.14, 51.78, 38.95, 28.79, 26.48, 25.04, 20.66, 19.99; HRMS (ESI) calcd. (M+H)⁺ for C₁₆H₂₆NO₆328.1760, found 328.1752.

EXAMPLE 14

Conversion of (16) to Salinosporamide A(1).

A solution of triol ester 16 (0.164 g, 0.5 mmol) in 3 N aq LiOH (3 mL) and THF (1 mL) was stirred at 5° C. for 4 days until hydrolysis was complete. The acid reaction mixture was acidified with phosphoric acid (to pH 3.5). The solvent was removed in vacuo and the residue was extracted with EtOAc, separated, and concentrated in vacuo to give the crude trihydroxy carboxylic acid 16a (not shown). The crude acid was suspended in dry CH₂Cl₂(2 mL), treated with pyridine (0.5 mL) and stirred vigorously at 23° C. for 5 min. To this solution was added BOPCl (152 mg, 0.6 mmol) at 23° C. under argon, and stirring was continued for 1 h. The solvent was removed under high vacuum and the residue was suspended in dry CH₃CN (1 mL) and treated with pyridine (1 mL). To this solution was added PPh₃Cl₂(333 mg, 1.0 mmol) at 23° C. under argon with stirring. After 1 h the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate-CH₂Cl₂, 1:5) to give the pure β-lactone 1 (100 mg, 64%) as a colorless solid.

R_f=0.55 (50% ethyl acetate in hexane). mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C. [α]²³ _D−73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357); FTIR (film) ν_max: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);¹³C NMR (CDCl₃, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00; HRMS (ESI) calcd. for (M−H)⁻ C₁₅H₁₉ClNO₄312.1003, found 312.1003.

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Name:		Marizomib
Synonyms:		6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-; Other Names: (-)-Salinosporamide A; ML 858; Marizomib; NPI 0052; Salinosporamide A
CAS Registry Number:		437742-34-2
Molecular Formula:		C15H20ClNO4
Molecular Weight:		313.1
Molecular Structure:

DARUNAVIR

December 24, 2013 12:16 pm / Leave a comment

DARUNAVIR

206361-99-1 CAS NO

[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester

M. P.:- 72-74 °C (dec)

MW: 547.66

Darunavir and processes for its preparation are disclosed in EP0715618, W09967417, EP1725566 and Bioorganic & Medicinal Chemistry Letters (2004), 14(4), 959-963.

J Med Chem. 2013 May 23;56(10):4017-27. doi: 10.1021/jm400231v

US20050250845 discloses various pseudopolymorphs of darunavir and processes for their preparation. According to this application, “pseudopolymorph” is defined as a crystalline form of a compound in which solvent molecules are incorporated in the lattice structure. The Form B disclosed in the patent application is a pseudopolymorph wherein water is used as solvent. The thermogravimetric experiments of the Form B shows weight loss of 3.4% in the temperature range 25-78°C (water), 5.1% in the temperature range 25-1 10°C (ethanol and water) and further 1.1% weight loss (ethanol) in temperature range 110-200° C. Further at the drying step the Form B showed about 5.6% weight loss. The obtained dried product was hygroscopic and it adsorbed up to 6.8% water at high relative humidity. Amorphous form of darunavir is disclosed in US20050250845 and the publication in J.Org. Chem. 2004, 69, 7822 – 7829.

US 7700645 patent disclosed amorphous Darunavir, various solvates of Darunavir including ethanolate and method for their preparation as well as their use as a medicament. Journal of Organic Chemistry 2004, 69, 7822-7829 disclosed amorphous Darunavir is obtained by purification with column chromatography in 2% methanol in chloroform as eluent. PCT publication WO2010086844A1 disclosed crystalline dimethylsulfoxide solvate and crystalline tetrahydrofuran solvate of darunavir. The publication also disclosed the amorphous darunavir having the IR spectrum with characteristic peaks at about 1454 and 1365 cm^“1

PCT publication WO201 1083287A2 disclosed crystalline darunavir hydrate substantially free of any non aqueous solvent.

Drug information:- Darunavir is an Anti-microbial drug further classified as anti-viral agent of the class protease inhibitor. It is used either single or in combination with other drugs for the treatment of human immunodeficiency virus.

Darunavir (brand name Prezista, formerly known as TMC114) is a drug used to treat HIV infection. It is in the protease inhibitor class. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.Developed by pharmaceutical company Tibotec, darunavir is named after Arun K. Ghosh, the chemist who discovered the molecule at the University of Illinois at Chicago. It was approved by the Food and Drug Administration (FDA) on June 23, 2006.^[2]

Darunavir is a second-generation protease inhibitor (PIs), designed specifically to overcome problems with the older agents in this class, such as indinavir. Early PIs often have severe side effects and drug toxicities, require a high therapeutic dose, are costly to manufacture, and show a disturbing susceptibility to drug resistant mutations. Such mutations can develop in as little as a year of use, and effectively render the drugs useless.

Darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs.

Darunavir received much attention at the time of its release, as it represents an important treatment option for patients with drug-resistant HIV. Patient advocacy groups pressured developer Tibotec not to follow the previous trend of releasing new drugs at prices higher than existing drugs in the same class. Darunavir was priced to match other common PIs already in use, such as the fixed-dose combination drug lopinavir/ritonavir.

PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV-1) protease.

PREZISTA (darunavir), in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C₂₇H₃₇N₃O₇S • C₂H₅OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:

PREZISTA (darunavir) Structural Formula Illustration

Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.

Patent

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CN102584844A *	Jan 11, 2011	Jul 18, 2012	浙江九洲药业股份有限公司	Darunavir crystal form and method for preparing same
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US7700645	May 16, 2003	Apr 20, 2010	Tibotec Pharmaceuticals Ltd.	Pseudopolymorphic forms of a HIV protease inhibitor

Reference
1		JOURNAL OF ORGANIC CHEMISTRY vol. 69, 2004, pages 7822 – 7829
2	*	VAN GYSEGHEM E ET AL: “Solid state characterization of the anti-HIV drug TMC114: Interconversion of amorphous TMC114, TMC114 ethanolate and hydrate“, EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER, AMSTERDAM, NL, vol. 38, no. 5, 8 December 2009 (2009-12-08), pages 489-497, XP026764329, ISSN: 0928-0987, DOI: 10.1016/J.EJPS.2009.09.013 [retrieved on 2009-09-24]

Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections. Darunavir has HIV protease inhibitory activity and is particularly well suited for inhibiting HIV-I and HIV -2 viruses. Darunavir, chemically (1 S^R.S’R.S’aS.e’aRJ-fS’he ahydrofuro^.S-b ]furanyl-[3-( 4-aminobenzenesulfonyl)isobutylamino [- 1-benzyl-zhydroxypropyl]carbamate. Darunavir is represented by the following structure:

Darunavir and its pharmaceutically acceptable salts were disclosed in US 6248775 patent, wherein Darunavir is prepared by condensing 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2- methylpropyl)amino]-1S(phenylmethyl)propylamine with hexahydro-furo[2,3-b]furan-3-ol in anhydrous acetonitrile in the presence of anhydrous pyridine and Ν,Ν’-disuccinimidyl carbonate at ambient temperature.

PCT publication WO201 1083287A2 disclosed crystalline darunavir hydrate substantially free of any non aqueous solvent.

Darunavir Ethanolate, has the chemical name: [(1 S, 2R)-3-[[(4-aminophenyl) sulfonyl](2- methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid (3/?, 3aS, 6a/?)- hexahydrofuro[2,3-i>]furan-3-yl ester monoethanolate and has the following structural formula:

Darunavir and its process are first disclosed in US 6248775, wherein 2 ?-hydroxy-3-[[(4- aminophenyl)sulfonyl](2-methylpropyl)amino]-1 S(phenylmethyl) propylamine (4) is reacted with (3R, 3aS, 6aR)-hexahydrofuro[2,3- >]furan-3-ol in anhydrous acetonitrile in the presence of N, W-disuccinimidyl carbonate, anhydrous pyridine at ambient temperature followed by workup to get Darunavir (Scheme A).

Scheme A

Darunavir

US 20050250845 disclosed the various solvates of Darunavir including ethanolate and method for their preparation as well as their use as a medicament. The same application disclosed the amorphous Darunavir by Raman spectra without process details.

WO 2005063770 discloses process for the preparation of Darunavir ethanolate, wherein 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1 S-(phenylmethyl)propyl amine (4) is reacted with (3R, 3aS, 6a ?)-hexahydrofuro[2,3-b]furan-3-ol in the presence of N, /V-disuccinimidyl carbonate, triethylamine, 41% methylamine in ethanol in a mixture of ethyl acetate and acetonitrile followed by workup and crystallization from ethanol to get Darunavir ethanolate (Scheme B).

Scheme B

In the prior art process, compound of formula 4 condensed with (3/?, 3aS, 6aR)- hexahydrofuro[2,3-6]furan-3-ol in large excess of solvent or solvent mixture containing large excess of base or mixture of bases to get Darunavir. Further, the obtained products by the processes described in the prior art are not satisfactory, from purity point of view. We have repeated the Darunavir synthetic procedures as described in the prior art and found that relatively large amounts of impurities were obtained along with Darunavir (Table-1) which need repeated crystallizations in different solvents to get desired quality of the final product resulting in poor yields. Among other impurities, the carbonic acid [(1/?,2S)-1-{((4-amino-benzenesulfonyl)-isobutyl-amino)-methyl}-2-((3R,3aS_I6aR)- hexahydro-furot2,3-/3]furan-3-yloxycarbonylamino)-3-phenyl-propylester (3R,3aS,6aR)- hexahydro-furo[2,3-ft]furan-3-yl ester (difuranyl impurity of formula 1) is identified.

Conditions:-

i. Phenyl magnesium bromide, Cuprous cyanide, tetrahydrofuran, 23 °C, 1 h,

ii. t-Butyl hydroperoxide, titanium tetraisopropoxide, diethyl D-tartrate, dichloromethane, -22 °C, 24 h,

iii. Azidotrimethylsilane, titanium tetraisopropoxide, Benzene, reflux, 25 min,

iv. 2-Acetoxyisobutyryl chloride, Chloroform, 23 °C, 8 h,

v. Isobutyl amine, isopropanol, 80 °C, 12 h,

vi 4-aminobenzenesulfonyl chloride, aq. Sodium bicarbonate, dichloromethane, 23 °C, 12 h,

vii. 10% palladium on carbon, hydrogen gas (50 psi), methanol, acetic acid, tetrahydrofuran, room temperature, 2 h,

viii. [3R, 3aS,6aS]-3-hydroxyhexahydrofuro[2,3-b]-furan, disuccanamidyl carbonate, triethylamine, acetonitrile, 23 °C, 12 h

Schematic Representation for Synthesis of Darunavir

Preparation of Darunavir is described in US patent 05,158,713, and also in WO9967417 and WO9967254. Accordingly, 2-vinyloxirane 1 on reacting with phenyl magnesium bromide in presence of tetrahydrofuran solvent and cuprous cyanide catalyst give 4-phenylbut-2-ene-1-ol 2. Oxidizing 2 with t-Butyl hydroperoxide in presence of titanium tetraisopropoxide and diethyl D-tartrate using dichloromethane as solvent give [(3S)-3-benzyloxiran-2-yl]methanol 3.

Heating 3 with azidotrimethylsilane in presence of titanium tetraisopropoxide using benzene as solvent give (2S,3S)-3-azido-4-phenyl-butane-1,2-diol 4. The 1,2-dipl compound 4 underwent cyclization when treated with 2-acetoxyisobutyryl chloride in chloroform give (2S)-2-[(1S)-1-azido-2-phenyl-ethyl]oxirane 5, which was further heating with isobutylamine and isopropanol at higher temperature give (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-butan-2-ol 6. Compound 6 was reacted with 4-aminobenzenesulfonyl chloride in presence of aq. Sodium bicarbonate as base and dichloromethane as solvent resulting in to 4-amino-N-[(2R,3S)-3-azido-2-hydroxy-4-phenyl-butyl]-N-isobutyl-benzenesulfonamide 7.

Hydrogenating 7 with 10% palladium on carbon catalyst using hydrogen gas (50 psi) in methanol and tetrahydrofuran solvent in presence of small amount of acetic acid at ambient temperature resulted in to 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl]-N-isobutyl-benzenesulfonamide 8. The final step involves reacting 8 with [3R,3aS,6aS]-3-hydroxyhexahydrofuro[2,3-b]-furan and disuccanamidyl carbonate in presence of triethylamine base and acetonitrile as solvent afford [(1S,2R)-3-[[(4-Aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester also called Darunavir 9.

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http://www.google.com/patents/WO2013114382A1?cl=en

process for the preparation of amorphous Darunavir is as

Process for the preparation of intermediate 2 is as shown in below scheme.

Examples

Example -1 : Preparation of [(1S, 2S)-3-chloro-2-hydroxy-1-(phenyl methyl) propyl] carbamic acid tert-butyl ester (5).

The solution of (3S)-3-(tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone (Chloromethyl ketone 6,100 g) and aluminium isopropoxide (35 g) in isoprpylalcohol was heated to mild reflux and maintained for 3 hours. After completion of reaction distilled off isopropyl alcohol up to 50 % under vacuum and the resultant mass was cooled to 25-35°C. Water was added to the distillate, pH was adjusted to 3.0-4.0 with acetic acid and maintained the stirring for 2 hours at 25-35°C. The obtained solid was filtered and washed with water. The wet cake was taken into isopropyl alcohol (400mL) and heated to reflux for 60minutes, the mass was cooled to 25-35°C again maintain the stirring for 60minutes, the obtained solid was filtered and washed with isopropyl alcohol. The wet product was dried under normal drying to get title compound 5 (yield 80 g). Example -2: Preparation of [(1 S, 2R)-3-[(2-methylpropyl) amino]-2-hydroxy-1- (phenylmethyl) propyl] carbamic acid tert-butyl ester (4).

The mixture of [(1S, 2S)-3-chloro-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid tert-butyl ester (5,100 g), isobutyl amine (294 g), sodium carbonate (31.3 g) and water was heated to 60 – 65°C and maintained for 3hours. After completion of reaction water (200 mL) was added and distilled out excess isobutyl amine under vacuum at below 75°C. Water (800 mL) was added to the distillate, cooled to 25-35°C and stirred for 2 hours. The obtained solid was filtered and washed with water to get title compound 4 (yield 105 g).

Example -3: Preparation of [(1S, 2R)-3-[[(4-nitrophenyl) sulfonyl] (2-methylpropyl) amino]- 2-hydroxy-1-(phenylmethyl) propyl] carbmic acid tert-butylester (3).

[(1 S, 2R)-3-[(2-methylpropyl) amino]-2-hydroxy-1 -(phenyl methyl) propyl] carbamic acid tert-butyl ester (4, 100 gm) and triethylamine (39.04 g) was added to methylenedichloride (1200 mL) and the temperature was raised to 40°C. p-nitro benzene sulfonyl chloride solution (72.3g of p-NBSC dissolve in 300mL methylenedichloride) was added slowly at 40-45°C for 2-3 hrs. The reaction was maintained for 3hours at 40 – 45°C. After completion of the reaction, water (500 mL) was added, separated the organic layer and distilled out methylene dichloride at atmospheric pressure. Finally, strip out the methylene dichloride by using isopropyl alcohol (200 mL). Isopropyl alcohol (1000 mL) was added to the distillate and maintained the stirring for 60 minutes at 70- 80°C. Cooled the mass to 30 – 35°C, filtered and washed with Isopropyl alcohol to get title compound 3 (yield 145 g). Example – 4: Preparation of 4-Amino-N-(2R, 3S) (3-amino-2-hydroxy-4-phenylbutyl)-N- isobutyl-benzene sulfonamide (1).

(1S, 2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3, 100g), 10% palladium carbon (10gm) and triethanolamine (2gm) were suspended in isopropyl alcohol. The reaction was heated to 40 – 45°C and maintained under 4 – 6kg/cm2 of hydrogen pressure for 3 hours. After completion of reaction, the mass was filtered and hydrochloric acid (70mL) was added to the filtered mass. The solution was heated to reflux and maintained for 2-3hours. After completion of reaction the mass was cooled to 25-35°C, the reaction mass pH was adjusted to 6.0 – 7.0 with 20% sodium hydroxide solution and distilled out isopropyl alcohol under vacuum at below 55°C. Ethanol (200mL) and water (400mL) was added to the distillate, the mass pH was adjusted to 9.0 – 10.0 with 20% sodium hydroxide solution at 25-35°C and maintained the stirring for 2 hours at 25-35°C. The mass was cooled to 0 – 5°C, filtered and wash with water. The wet product was taken into ethanol (350mL), maintained the stirring for 30minutes at reflux temperature. The mass was cooled to 2 – 4°C, stirred for 2 hours, filtered and washed with ethanol (50 mL). The wet product was dried under normal drying to get title compound 1 (Yield 60 g).

Example-5: Preparation of ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (VI).

2, 3-Dihydrofuran (250 g) was taken in toluene (2000 mL) and triethyl amine (505 g) was added to above solution. Ethyl oxalyl chloride (536.5 g) was slowly added to the above mixture by maintaining temperature at 25-30°C and maintained the stirring for 5 hours. After completion of reaction separated the organic layer, washed the organic layer with 8% sodium bicarbonate solution (2x500mL). Organic layer was distilled completely under vacuum to get title compound VI (Yield 560g).

1 H NMR : 1.38 (t, 3H), 2.93 (t, 2H), 4.34 (q, 2H), 4.63 (t, 2H), 8.02 (s, 1 H).

Example-6: Preparation of ethyl-2-(3-bromo-2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (V).

Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (Vl, 100g) was dissolved in dichloromethane (500ml) and Ethanol (150mL) was added. The reaction mass was cooled to 5 to 10°C. N- bromosuccinimide (1 15 g) was added lot wise by maintaining temp below 10°C. Reaction mass was then stirred at 20-30°C till completion of reaction. Reaction mass was washed with sodium bicarbonate solution (2%, 3x400mL) and the organic layer was used for the next step.

Example-7: Preparation of hexahydrofuro [2, 3-b] furan-3-ol (IV).

To the solution of Ethyl-2-(3-bromo-2-ethoxy tetra hydrofuran-3-yl)-2-oxoacetate in dichloromethane (V, 500mL) as prepared in above example, sodium sulphite solution (225g was dissolved in 1700mL of water) was added at 25-35°C. Reaction mass was stirred for 5-8hours at the same temperature and separated the organic and aqueous layers. Organic layer was washed with water (340mL). Distilled out the solvent completely get ethyl-2-(2-ethoxy tetra hydrofuran-3- yl)-2-oxoacetate. Sodium borohydride (35.5g)was dissolved in ethanol (400mL) under nitrogen atmosphere, ethyl-2-(2-ethoxytetra hydrofuran-3-yl)-2-oxoacetate was dissolved in ethanol (100mL) and slowly added to above solution at 15-30°C. Reaction mass was heated to 30-45X, maintained for 5-8 hours, the reaction mass temperature was raised to 55°C and stirred for 8 hours. The reaction mass was cooled to 20-30°C, ammonium chloride solution (1 5g in 200mL water) was slowly added and stirred for 1-2hours. The reaction mass was filtered and filtrate was distilled out under vacuum to get residue. Dichloromethane (600mL) was added to residue and cooled to -10°C. Hydrochloric acid (85mL) was added slowly drop wise in 2 hours by maintaining temp -5 to 0°C, reaction mass was stirred for 60minutes at -5 to 0°C and distilled the solvent completely. The obtained residue was stripped out with isopropyl alcohol (2x200mL, 1x100mL), ethyl acetate (500mL) was added to the resultant residue, stirred for 30-60minutes and cooled to 10-15°C. The solution was filtered and filtrate was concentrated to get title compound IV (yield 56 g).

Example-8: Preparation of Hexahydrofuro [2, 3-b] furan-3-yl acetate (III).

Hexahydrofuro [2, 3-b] furan-3-ol (IV, 60g) was dissolved in dichloromethane (300mL) and cooled to 0-5°C. To the cooled solution triethylamine (58.2 g), N, N-dimethylaminopyridine (1.12g) was added, acetic anhydride (56.5g) was added for 30-60 minutes at the same temperature, the mass temperature was raised to 25-35°C and stirred for 2-4hours. After completion of reaction the mass was cooled to 10-20°C, water (120mL) was added, stirred for 30minutes, separated the organic layer, washed with 10% sodium chloride solution (120mL) and distilled out dichloromethane to get title compound (yield 72g). Further, the product was purified by fractional distillation to get pure Hexahydrofuro [2, 3-b] furan-3-yl acetate III (yield 54g).

1 H NMR : 1.9-2.09(m, 2H), 2.10(s, 3H), 3.0-3.1 (m, 1 H), 3.86-4.03(m, 2H), 3.73(dd, 1 H), 4.10(dd, 1 H), 5.19(m, 1 H), 5.72 (d, 1 H)

Example-9: Preparation of (3R, 3aS, 6aR)-Hexahydrofuro [2, 3-b] furan-3-yl acetate (II). To the buffer solution (104.3g of sodium dihydrogen orthophosphate dissolved in 530mL of water & pH adjusted to 6.0-6.5 with saturated sodium bicarbonate solution(68g in 680 mL water) solution) hexahydrofuro [2, 3-b] furan-3-yl acetate (111,115g) and CAL-B (17.25g) was added at 25-35°C, heated to 38-45°C and stirred for 24 hours. CAL-B (17.25g) was added stirred for 16 hours, again CAL- B (11.5g) was added at 38-45°C and stirred for 16 hours (pH should maintain 6.0-6.5). The reaction mass was cooled to 20-30°C, methylenedichloride (1 150mL) was added to the mass and stirred for 30 minutes. The reaction mass was filtered through hyflowbed then separated the organic layer and washed with 10%sodiumchloride solution (575mL). Organic layer was distilled completely under vacuum to get title compound II (yield 40. Og). Example-10: Preparation of (3R, 3aS, 6aR)-Hexahydrofuro [2, 3-b] furan-3-ol (I).

(3R, 3aS, 6aR)-Hexahydrofuro [2, 3-b] furan-3-yl acetate (II, 14.0g) was dissolved in methanol (42mL). Potassium carbonate (0.34g) was added and stirred at 25-35°C for 6-8hours. Methanol was distilled out completely under vacuum, to the distillate methylenedichloride (28mL) was added, stirred the mass for 30 minutes and again distilled the solvent to get residue. Dissolved the residue in dichloromethane (56mL), the resultant solution was treated with carbon and the solvent was completely distilled out get title compound I (yield 10.5g). Example-11 : Preparation of (3R, 3aS, 6aR)-Hexahydrofuro [2, 3-b]-furan-3-yl-4-nitrophenyl carbonate (2).

To the solution of (3R, 3aS, 6aR)-Hexahydrofuro [2, 3-b] furan-3-ol (l,100g) and Bis-nitrophenyl carbonate (257.2g) in methylene dichloride (1200mL), triethylamine solution (132 g in 300 mL of methylene dichloride) was added slowly at 20-30°C for 2-3hours. Maintained the reaction at the same temperature for 8-10hours, after completion of reaction water (500mL) was added for 30- 60minut.es and settled the reaction mass then separated the organic layer. Organic layer was washed with 10% acetic acid (100mL) and 10% sodium chloride solution (500mL), distilled the organic layer and co distilled with ethyl acetate (100mL). Ethyl acetate (300mL) was added to the distillate and heated to 50-55°C for 30-45minut.es to get clear solution, the solution was cooled to 5-10°C and maintained at the same temperature for 60 minutes. The obtained solid was filtered, washed with ethanol (100mL) and dried the wet material at 40-45°C for 10-14 hours to get title compound 2 (yield 160g). Example-12: Preparation of dimethylformamide solvate of Darunavir.

To a mixture of 4-amino-N-(2r,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-lsobutyl- benzenesulfonamide (1 ,25g) and N-methyl-2-pyrrolidinone (NMPO, 50mL), a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]-furan-3-yl-4-nitrophenyl carbonate (2, 8.85g) and N-methyl- 2-pyrrolidinone (75mL) was added at -5 to 0°C for 2 to 3 hours under nitrogen atmosphere. The mass temperature was slowly raised to 25 to 30°C and stirred for 6 to 8 hours. The reaction mass was quenched in to the solution of methylene chloride (125mL) and water (250mL) at 25-35°C for 30 to 45 minutes. Separated the organic layer followed by washed with 10% sodium carbonate solution (150mL), 10% sodium chloride solution (150mL) and with water (6x150mL). Organic layer was dried over sodium sulphate and distill off the solvent under vacuum at below 50°C to obtain darunavir as a residue. To the residue Ν,Ν-dimethyl formamide (50mL) was added and cooled to 0 to -5°C, water (25mL) was added to the solution and maintained for 12hours at 0 to -5 °C, the obtained solid was filtered and washed with pre-cooled mixture of N,N-dimethyl formamide & water (25mL+25mL) to get dimethylformamide solvate of darunavir.

Example-13: Preparation of non-solvated crystalline Darunavir.

To a mixture of 4-amino-N-(2r,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-lsobutyl- benzenesulfonamide (1, 25g) and N-methyl-2-pyrrolidinone (NMPO, 50mL), a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]-furan-3-yl-4-nitrophenyl carbonate (2, 18.85g) and N- methyl-2-pyrrolidinone (75mL) was added at -5 – 0°C for 2 to 3 hours under nitrogen atmosphere. The mass temperature was slowly raised to 25 – 30°C and stirred for 6 to 8 hours. The reaction mass was quenched in to the solution of methylene chloride (250mL) and water (250mL) at 25- 35°C for 30 – 45 minutes. Separated the organic layer followed by washed with 10% potassium carbonate solution (5x125mL), water (5x125mL), 20% sodium chloride solution (25mL), finally washed with 20% citric acid solution (125mL). The organic layer was treated with carbon and distilled off the solvent under vacuum at below 50°C to obtain darunavir as a residue. To the residue ethylacetate (250mL) was added and cooled to 0 to -5°C, to the cooled solution hexane (225mL) was added and maintained for 12hours at 0 to -5 °C, the obtained solid was filtered, washed with pre-cooled mixture of ethylacetate and hexane (25mL+25mL) and dried the compound to get non-solvated crystalline darunavir(yield 25g).

Example -14: Preparation of Amorphous Darunavir.

Darunavir (200g) as obtained in above example was dissolved in methylene dichloride (10L) and washed with water (3×1000 mL). Organic layer was taken into agitated thin film dryer (ATFD) feed tank. Applied initial temperature about 36 – 40°C and high vacuum (580mm/Hg) to the vessel. Slowly feed the solution to the Vessel (feed rate 5L r) over 1hour finally given the methylene chloride (3L) flushing. The material is collected in the material collecter. Dried at 58 -62°C for 40 hours to get amorphous darunavir (yield 160g).

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http://www.google.com/patents/WO2011048604A2?cl=en

Preparation of Durumvir ethanolate

A solution of (3R,3aS,6a ?)-hexahydrofuro[2,3-D]furan-3-yl 4-nitrophenyl carbonate (5b, 75.4 g) in A -methyl-2-pyrrolidinone (300 mL) was added to a pre-cooled (-2 ± 2°C) solution of the compound of formula 4 (100 g) in W-methyl-2-pyrrolidinone (200 mL) at -4 to 0°C over a period of 2 h. The temperature of the reaction mass was slowly raised to 25 – 30°C and maintained for 8 h. After completion of the reaction (TLC monitoring), ethyl acetate (1000 mL) and purified water (500 mL) were added to the reaction mass. The layers were separated; organic layer was washed with sodium carbonate solution (2 X 500 mL) followed by sodium chloride solution. The organic layer was concentrated; ethanol (300 mL) was added, heated to 45 – 50°C, maintained for 1 h, filtered and washed with ethanol. The wet compound was taken into a mixture of ethyl acetate- ethanol (7:93, 600 mL), heated to reflux, charcoal was added and filtered. The resultant filtrate was cooled to 0 – 5°C, filtered the separated solid and washed with ethanol. The wet compound was dried at 45°C to obtain the in 124.3 g (yield-82.5%). The obtained Darunavir ethanolate had purity of 99.79% on area by HPLC and contained 0.08% on area by HPLC of the difuranyl impurity. Preparation of Amorphous Darunavir

Example – 4

A solution of Darunavir ethanolate (200 g) in dichloromethane (10 L) was taken into ATFD Feed tank. The solvent was evaporated by fed the solution slowly to the ATFD Vessel (feed rate 5 L /h) at 36 – 40°C and high vacuum (580 mm/Hg) over 2 h and then flushed with dichloromethane (3 L). The material is collected in the material collector in 160g with the HPLC Purity of 99.60% and particle size D₅₀ of approximately 50 micrometers and D_go of approximately 100 to 180 micrometers. Example-5

Darunavir Ethanolate (200 gm) was dissolved in Methylene chloride (1000 ml) and solvent was evaporated by applying vacuum followed by isolation of amorphous Darunavir as a solid as such or by charging n-Heptane or Isopropyl ether. Example – 6

Darunavir Ethanolate (10 g) was dissolved in ethyl acetate (50 mL). The solution was heated to 40 – 45°C and maintained for 30 min. Ethyl acetate was distilled off under vacuum completely to get residue in the form of semisolid. n-Heptane (50 mL) was added to the residue and stirred for 30 min. at ambient temperature. The separated solid was filtered, washed the wet cake with n-heptane (5 mL) and dried at 40 – 45°C under vacuum to get 8.0 g of amorphous Darunavir.

Example – 7

Darunavir Ethanolate (10 g) was placed into a dry round bottom flask and heated to 110 – 120°C to melt and maintained under vacuum for 4 h. The reaction mass was slowly cooled to 25 – 35°C. The obtained glass type crystal was broken into powder to afford 8.5 g of amorphous Darunavir.

Example – 8

Darunavir Ethanolate (5.0 g) was suspended into glycerol (25 g), heated to 110 – 120°C under vacuum and maintained for 30min. Water (50 mL) was added to the cooled reaction mass at 25 – 35°C under stirring and the obtained suspension was stirred for 30 min at 25 – 35°C. The separated solid was filtered and dried at 40 – 45°C under vacuum to yield 3.5 g of amorphous Darunavir. Example – 9

Carbonic acid [(1 R,2S)-1-{((4-amino-benzenesulfonyl)-isobutyl-amino)-methyl}-2- ((3/?,3aS,6aR)-hexahydro-furo[2,3-ft]furan-3-yloxycarbonylamino)-3-phenyl-propylester (3R,3aS,6a ?)-hexahydro-furo[2,3- )]furan-3-yl ester (difuranyl impurity, 1).

The difuranyl impurity (1) isolated from the mother liquor by preparative HPLC using a mixture of formic acid-water (1 :99) as eluent. The ¹H-NMR, ¹³C-NMR and mass spectral data complies with proposed structure.

¹H-NMR (DMSO-cfe, 300 MHz, ppm) – δ 0.79 (d, J=6.6 Hz, 6H, 15 & 15′), 1.14-1.20 (m, 1 H, 20Ha), 1.34-1.42 (m, 1 H, 20Hb), 1.75-1.85 (m, 2H, 20’Ha & 14), 1.94-2.01(m, 1 H, 20’Hb), 2.54-2.64 (m, 2H, 8Ha & 13Ha), 2.74-2.89 (m, 3H, 8Hb, 13Hb & 19), 3.00-3.11 (m, 2H, 5Ha & 19′), 3.34-3.39 (m, 1H, 5Hb), 3.54-2.63 (m, 3H, 21 Ha & 17Ha), 3.65-3.74 (m, 3H, 21’Ha, 21 Hb &17Hb), 3.81-3.89 (m, 2H, 21’Hb & 17’Ha), 3.94-4.04 (m, 2H, 7 & 17’Hb), 4.81-4.88 (m, 1 H, 6), 4.92-4.96 (m, 1 H, 18′), 5.03-5.10 (m, 1 H, 18), 5.11 (d, J=5.4 Hz, 1 H, 22′), 5.61 (d, J=5.1 Hz, 1 H, 22), 6.03 (brs, 2H, NH₂, D₂0 exchangeable), 6.63 (d, J=8.7 Hz, 2H, 2 & 2″), 7.15-7.28 (m, 5H, 10H, 10Ή, 11 H, 11′ & 12), 7.40 (d, J=8.7 Hz, 2H, 3 & 3′), 7.55 (d, J=9.3 Hz, 1 H, NH, D₂0 exchangeable).

“H-NMR (DMSO-d₆, 75 MHz, ppm)- δ 19.56 & 19.81 (15C & 15’C), 25.42 (20 ), 25.47 (20C), 26.28 (14C), 35.14 (8C), 44.45(19’C), 45.01 (19C), 49.21 (5C), 53.39 (7C), 57.55 (13C), 68.70 (21 ‘C), 68.74 (21C), 69.95 (17’C), 70.20(17C), 72.65 (6C), 76.27 (18C), 79.59 (18’C), 108.70 (22’C), 108.75 (22C), 112.69 (2C), 122.56 (4C), 126.12 (12C), 128.04 (11 C & 11’C), 129.03 (10C & 10’C), 129.08 (3C), 138.03 (9C), 152.99 (1C), 153.55 (16’C), 155.32 (16C).

DIP MS: m/z (%) 1108 [M+Hf, 1131 [M+Naf

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http://www.google.com/patents/US20130244297

According to the present invention Darunavir having the below impurity not more than 0.1, preferably 0.05%.

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DARUNAVIR

Necitumumab

November 13, 2013 11:54 am / 1 Comment on Necitumumab

Necitumumab

Necitumumab is a fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR), which is a target in several anti-cancer treatments because it sparks cancer progression, both by promoting angiogenesis, or the formation of new blood vessels for tumors, and by inhibiting apoptosis, or cell death. Recently approved therapies for non-squamous NSCLC, including afatinib and erlotinib, target specific EGFR mutations, but those drugs are used to treat patients with nonsquamous histology.Lilly did not provide specific data regarding the results of the trial, but the company announced that it plans to present that data at a scientific meeting next year, and to request a review of the drug by regulatory authorities before the end of 2014.

Necitumumabis one of three monoclonal antibodies in Phase III
development that targets EGFR, the target of the approved antibodies
cetuximab and panitumumab. However, necitumumab is a fully human
IgG1 antibody, distinguishing it from both the approved agents.
Necitumumab is directed against the ligand binding site of EGFR and is
being co-developed by Eli Lilly and Bristol-Myers Squibb in the United
States, Canada, and Japan, while Eli Lilly alone is developing it for other
markets. Necitumumabfirst entered clinical development in 2004 and
is now in Phase III development for the treatment of non–small-cell
lung cancer and Phase II for the treatment of colorectal cancer. The
primary indication chosen further distinguishes necitumumabfrom both
cetuximab and panitumumab, but it is an indication for which EGFR
kinase inhibitors such as erlotinib are approved.
In December 2009, Eli Lilly stressed the long half-life of necitumumab
(7–10 days, which permits dosing at 2–3 week intervals) and its potential
both for reduced hypersensitivity reactions (i.e., better tolerability) and
for induced host-mediated anticancer activity. In addition, it highlighted
that necitumumabdisplays similar or superior activity to cetuximab
in anticancer models. Preliminary data were presented from the Phase
II study in colorectal cancer showing antitumor activity in 73% of 44
patients treated with necitumumabplus FOLFOX.
Both Phase III studies in non–small-cell lung cancer are in stage IV
disease and in groups of 947 patients treated with necitumumabplus
cisplatin and a second agent. The INSPIRE study in non-squamous
disease began in November 2009 and uses pemetrexed as the second
drug, while the SQUIRE study commenced in January 2010 in
squamous disease and uses gemcitabine. Both studies have primary
completion dates in late 2011 and study completion dates of mid-2012,
which points to BLA submission in 2013.

A Phase I study in patients with solid tumors suggested that skin
toxicity was the dose-limiting toxicity and suggested that 800 mg of
necitumumab (at weekly or fortnightly intervals) be the maximum dose
(Kuenen et al. 2010).16 This dose was employed in the initial colorectal
cancer study, at 14-day intervals, which revealed a 60% partial response
(Taberno et al. 2008).17
The development strategy for necitumumab appears to have been
designed to establish it initially in a major indication where it will not
be competing with established antibody products, while seeking
to exploit the reported advantages over cetuximab appears to be
a secondary priority. While the reported Phase II data are very
encouraging, it will be some time before a better assessment of the
commercial prospects of necitumumab can be made. However, it does
appear to have significant potential.

Necitumumab (proposed INN) is a monoclonal antibody and an antineoplastic. It binds to the epidermal growth factor receptor(EGFR).^[1] As of October 2009, two Phase III clinical trials are planned to investigate its effects on non-small cell lung carcinoma.^[2]^[3]

Possible Efficacy Of Lilly’s Necitumumab (IMC-11F8) In Lung Cancer Subset

18.4 2013

Eli Lilly announced yesterday their very preliminary and non-quantitative conclusions on the SQUIRE study, a 1093-patient Phase III trial of their anti-epidermal growth factor receptor (EGFR) antibody, necitumumab (IMC-11F8), against Stage IV squamous, non-small cell lung carcinoma (NSCLC).http://www.forbes.com/sites/davidkroll/2013/08/14/possible-efficacy-of-necitumumab-imc-11f8-in-squamous-nsclc-lung-cancer-subset/

Ixabepilone for breast cancer

November 12, 2013 12:47 pm / 1 Comment on Ixabepilone for breast cancer

Ixabepilone, 219989-84-1 cas

(1R,5S,6S,7R,10S,14S,16S)-6,10-dihydroxy-1,5,7,
9,9-pentamethyl-14-[(E)-1-(2-methyl-1,3-thiazol-
4-yl)prop-1-en-2-yl]-17-oxa-13-azabicyclo[14.1.0]
heptadecane-8,12-dione

Ixabepilone (INN; also known as azaepothilone B, codenamed BMS-247550) is an epothilone B analog developed byBristol-Myers Squibb as a chemotherapeutic medication for cancer.

It is produced by Sorangium cellulosum.

It acts to stabilize microtubules. It is highly potent agent, capable of damaging cancer cells in very low concentrations, and retains activity in cases where tumor cells are insensitive to paclitaxel.

On October 16, 2007, the U.S. Food and Drug Administration approved ixabepilone for the treatment of aggressive metastaticor locally advanced breast cancer no longer responding to currently available chemotherapies. In November 2008, the EMEAhas refused a marketing authorisation for Ixabepilone.

Ixabepilone is administered through injection, and is marketed under the trade name Ixempra.

patent approval expiry

United States	7312237	2004-08-21	2024-08-21
United States	6605599	1998-05-26	2018-05-26

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	Type	RLD	US Patent No.
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	RE41911*PED
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	RE41393*PED
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	7,312,237*PED
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	7,125,899*PED

Patent No	Patent Expiry	patent use code
6670384	Jan 23, 2022	U-959
6670384	Jan 23, 2022	U-960
6670384*PED	Jul 23, 2022
7022330	Jan 23, 2022	U-958
7022330*PED	Jul 23, 2022
7125899	May 26, 2018	U-957
7125899*PED	Nov 26, 2018
7312237	Aug 21, 2024	U-965
7312237*PED	Feb 21, 2025
RE41393	Feb 8, 2022	U-961
RE41393*PED	Aug 8, 2022
RE41911	Sep 28, 2020	U-961
RE41911*PED	Mar 28, 2021

Exclusivity Code	ExclusivityDate
NCE	Oct 16, 2012
PED	Apr 18, 2015
M-61	Oct 18, 2014
PED	Apr 16, 2013

Exclusivity Code	ExclusivityDate
NCE	Oct 16, 2012

Ixabepilone, in combination with capecitabine, has demonstrated effectiveness in the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane.

It has been investigated for use in treatment of non-Hodgkin’s lymphoma. In pancreatic cancer phase two trial it showed some promising results (used alone). Combination therapy trials are ongoing.

Ixabepilone is an anti cancer agent acting as a microtubule inhibitor, and which in particular are efficient in the treatment of cancer not reacting to other anti cancer agents, such as e.g. paclitaxel. Ixabepilone is marketed under the trade name Ixempra® and are approved for the treatment of aggressive metastatic or locally advanced breast cancer which not responding to the current prevailing chemotherapies.

Ixabepilone known under the CAS no. 219989-84-1 has the following structure:

Ixabepilone

Ixabepilone may be prepared from a starting material named epothilone B having the structural formula:

Epothilone B Ixabepilone as a compound is described in the USRE4191 1. USRE4191 1 furthermore disclose a process for synthesizing Ixabepilone.

The US 6,365,749 describes a process for making ixabepilone by reacting epothilone B with a palladium catalyst in the presence of a nucleophilic donor.

The USRE39356 do also describe a process for making Ixabepilone by reacting epothilone B with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst.

Ixabepilone is the treatment of metastatic and advanced breast cancer drugs.Ixabepilone as anticancer drugs alone or in combination with capecitabine (Capecitabine) in combination. October 16, 2007 approved for marketing by the FDA, trade name Ixempra, by the Bristol-Myers Squibb Company’s development.
Ixabepilone is an anti-mitotic drugs that are inhibitors of tubulin, the mechanism and paclitaxel (Taxol) the same class of drugs. Epothilone (Epothilone) by colistin (myxobacterium) Sorangium cellulosum fermentation of several macrolide metabolites in general. Anticancer activity in vitro experiments, epothilone A and epothilone B showed good activity, even in the paclitaxel-resistant cells also showed good activity. But its activity in vivo experiments in general, this is probably due to the body of the ester hydrolases that macrolide ring opening induced inactivation. In a series of epothilone derivatives activity test, it was found with the lactam bond instead of the original product of ester bonds – ixabepilone anticancer activity can be well retained.
Ixabepilone is epothilone B semi-synthetic derivatives. Epothilone B is a macrocyclic lactone, a hydroxyl moiety is allyl alcohol, the Pd catalyst can be obtained by ring-opening Pd complexes 1 , 1 received azide nucleophile attacking the anion generated with three azide product phosphorus reduction to give methyl amino acids 2 . Here we must point out that the attack was completely azide stereoselectivity, which is determined by two consecutive trans-attack lead, Pd (0)-trans lactone generate offensive allyl Pd complexes, to accept anti-azide anion type attack, to maintain the configuration of the product obtained. Amino acids 2 HoBt and EDCI generated by an amide bond to get ixabepilone.

IXEMPRA (ixabepilone) is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones and their analogs. The epothilones are isolated from the myxobacterium Sorangium cellulosum. Ixabepilone is a semisynthetic analog of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone.

The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]17-oxa-4-azabicyclo[14.1.0] heptadecane-5,9-dione, and it has a molecular weight of 506.7. Ixabepilone has the following structural formula:

IXEMPRA® Kit (ixabepilone) Structural Formula Illustration

IXEMPRA (ixabepilone) for injection is intended for intravenous infusion only after constitution with the supplied DILUENT and after further dilution with a specified infusion fluid . IXEMPRA (ixabepilone) for injection is supplied as a sterile, non-pyrogenic, single-use vial providing 15 mg or 45 mg ixabepilone as a lyophilized white powder. The DILUENT for IXEMPRA is a sterile, non-pyrogenic solution of 52.8% (w/v) purified polyoxyethylated castor oil and 39.8% (w/v) dehydrated alcohol, USP. The IXEMPRA (ixabepilone) for injection and the DILUENT for IXEMPRA are co-packaged and supplied as IXEMPRA Kit.

….

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DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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Possible Efficacy Of Lilly’s Necitumumab (IMC-11F8) In Lung Cancer Subset

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On October 16, 2007, the U.S. Food and Drug Administration approved ixabepilone for the treatment of aggressive metastaticor locally advanced breast cancer no longer responding to currently available chemotherapies. In November 2008, the EMEAhas refused a marketing authorisation for Ixabepilone.

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