WO2001046451A1 - Migrastatine, procede de production et compositions medicales correspondants - Google Patents

Migrastatine, procede de production et compositions medicales correspondants Download PDF

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Publication number
WO2001046451A1
WO2001046451A1 PCT/JP2000/009147 JP0009147W WO0146451A1 WO 2001046451 A1 WO2001046451 A1 WO 2001046451A1 JP 0009147 W JP0009147 W JP 0009147W WO 0146451 A1 WO0146451 A1 WO 0146451A1
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WIPO (PCT)
Prior art keywords
mygrass
cells
medium
culture
strain
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PCT/JP2000/009147
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English (en)
Japanese (ja)
Inventor
Tomio Takeuchi
Tsutomu Sawa
Masa Hamada
Hiroshi Naganawa
Yoshigazu Takahashi
Masaya Imoto
Kouichi Nakae
Original Assignee
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai filed Critical Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Priority to AU24014/01A priority Critical patent/AU2401401A/en
Publication of WO2001046451A1 publication Critical patent/WO2001046451A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces

Definitions

  • the present invention relates to migrastat in, a novel bioactive substance having an inhibitory activity on cell motility and an antitumor activity, and an activity on inhibiting angiogenesis.
  • the present invention also relates to a cell motility inhibitor comprising mygrass sutin, and a pharmaceutical composition comprising migras sutin as an active ingredient. Further, the present invention relates to a method for producing mygrass. Further, the present invention includes Streptomyces sp. MK929-43F1 strain or a mutant strain thereof as a novel microorganism.
  • cancer cells first detach due to cell movement from the primary focus.
  • angiogenesis angiogenesis is initiated by the movement of vascular endothelial cells. Therefore, a substance that can inhibit cell motility is expected to inhibit cancer metastasis and angiogenesis.
  • Such inhibitors of cell motility are expected to be useful as tools or reagents for elucidating the mechanisms of cell motility and angiogenesis.
  • An object of the present invention is to provide a new substance having an activity of inhibiting cell motility and exhibiting an antitumor activity or an anticancer activity.
  • the present inventors have conducted various studies for the purpose of discovering and providing a novel substance having cell motility inhibitory activity and antitumor activity or anticancer activity as described above.
  • mygrass sutin a novel compound represented by the formula (I)
  • mygrass sutin exhibits a growth inhibitory activity of various human cancer cells or tumor cells or a cancer cell killing activity, and has a motility of human cancer cells. It has been found that the compound has an inhibitory activity, further inhibits the motility of human vascular endothelial cells, and inhibits angiogenesis by inhibiting the ability to form a lumen.
  • Mygrass sutin according to the present invention has antitumor activity and also has an inhibitory activity on the motility of cancer cells. Therefore, migrass sutin is useful as an antitumor agent or an anticancer agent. Useful as a motility inhibitor.
  • mygrass sutin can be used as a cell motility inhibitor as a means to elucidate the mechanism of cell motility in cell carcinogenesis.
  • mygrass sutin has an activity of inhibiting the motility and tube forming ability of human vascular endothelial cells, and is therefore expected to be useful as an angiogenesis inhibitor.
  • the Rf value when developed with chloroform-methanol (10: 1) as the developing solvent is 0.45.
  • cancer cells acquire metastatic ability by becoming malignant. It is essential that cells have cell motility as one of the factors that cells acquire the metastatic ability. It is known that cancer cells that have acquired metastatic potential first detach from the cancer by moving from the primary tumor.
  • Test Examples 3 and 4 demonstrate that Mygrass-tin has the activity of inhibiting the motility of cancer cells.
  • a suspension of human umbilical vein endothelial cells was prepared in a 10% FCS-box 131 medium containing 10 ng / ml bFGF (basic fibroblast growth factor) at 4 lxlO / well and collagen coated. And spread them in a 96-well microplate. After culturing for 2 days and confirming that endothelial cells had grown on the entire surface of the bottom of the microplate, the cells were linearly peeled off from the bottom surface using a tip of a microphone orifice. After removing the medium, the cells were washed twice with PBS.
  • FCS-box 131 medium containing 10 ng / ml bFGF (basic fibroblast growth factor) at 4 lxlO / well and collagen coated. And spread them in a 96-well microplate. After culturing for 2 days and confirming that endothelial cells had grown on the entire surface of the bottom of the microplate, the cells were linearly peeled off from the bottom
  • mygrass-tin inhibited the migration of HUVEC cells at a concentration of 25 g / ml or more.
  • HUVEC cells human umbilical vein endothelial cells
  • FGF fibrob 1 ast growth factor
  • tube formation of HUVEC cells was completely inhibited by 3.0 g / ml of mygrass-tin.
  • the cell growth inhibitory activity of HUVEC cells was also examined in the same manner as in Test Example 1 above. As a result, mygrass-tin showed a cell growth inhibitory activity on HUVEC cells in a concentration-dependent manner. In this case, the IC 50 of Mygrass was 3.0 ⁇ g / ml.
  • the mygrass protein of the present invention was also shown to have an activity of inhibiting angiogenesis by vascular endothelial cells.
  • Mygrass Yutin inhibited A and protein synthesis by 50% at a concentration of 60 to 75 ⁇ g / ml without inducing DNA synthesis in human small cell lung cancer Ms-1 cells.
  • a solution was prepared by dissolving Mygrass Yutin in physiological saline containing 10% dimethyl sulfoxide and Tween 80, and the solution was injected into the vein of mice. For 14 days. As a result, mygrass-tin did not show toxicity at the intravenous administration of 100 mg / kg.
  • the mygrass-tin according to the first aspect of the present invention has various biological activities as described above.
  • a second cell motility inhibitor according to the present invention comprising Mygrass-tin Alternatively, it is used as a reagent for elucidating the mechanism of cell movement in angiogenesis of vascular endothelial cells, and has the potential to be used as a therapeutic agent targeting cancer metastasis or angiogenesis.
  • composition comprising as an active ingredient a mygrass sutin.
  • the third pharmaceutical composition of the present invention can be in the form of an antitumor agent or an angiogenesis inhibitor.
  • a carrier that can be mixed with mygrass dinner as an active ingredient can be blended.
  • the carrier can be a pharmaceutically acceptable solid or liquid carrier, such as starch, lactose, water, ethanol, hydrous ethanol.
  • the administration of migras sutin can be carried out by any suitable route of administration, and in a dosage determined by the adopted route of administration. it can.
  • the administration can be performed by changing the route. It is usually administered in the form of a preparation diluted with a pharmaceutically acceptable carrier or diluent.
  • the formulation will contain 0.01-100%, preferably 0.1-70%, by weight of mygrass protein, with the balance comprising a pharmaceutically acceptable carrier and other adjuvants.
  • one typical administration method is to inject mygrass sutin as a solution dissolved in distilled water for injection or physiological saline.
  • mygrass sutin as a solution dissolved in distilled water for injection or physiological saline.
  • methods such as intraperitoneal injection, subcutaneous injection, intravenous injection into veins and arteries, and local administration by injection can be used.
  • the dose of Mygrass evening dose is determined in consideration of various situations so that the total dose does not exceed a certain amount when administered continuously or intermittently. It is about 800mg.
  • Specific dosages will vary depending on the method of administration, the condition of the patient or treated animal, e.g., age, weight, sex, susceptibility, diet, time of administration, concomitant medications, patient or degree of disease. Needless to say. Under certain conditions, the appropriate dose and frequency of administration of Mygrass evening tin must be determined by a specialist's dosage determination test based on the above guidelines.
  • a fourth aspect of the present invention is characterized in that a bacterium belonging to the genus Streptomyces and producing the mygrass sutin represented by the formula (I) is cultured in a medium, and mygrass sutin is collected from the culture.
  • the following equation (I) is characterized in that a bacterium belonging to the genus Streptomyces and producing the mygrass sutin represented by the formula (I) is cultured in a medium, and mygrass sutin is collected from the culture.
  • the manufacturing method of the mygrass resin shown by these is provided.
  • mygrasstin (migrastatin) -producing bacterium used in the fourth method of the present invention for producing mygrasstin is described in January 1998 in the Institute for Microbial Chemistry in the soil of Atami City, Shizuoka Prefecture. This is an actinomycete isolated from MK929-43 ⁇ with a strain number of MK929-43 ⁇ .
  • the MK929-43 ⁇ strain elongates aerial hyphae which are relatively longer than the branched basal hyphae to form ring-shaped branches.
  • Mature spore chains link 3 to 10 cylindrical spores.
  • the spores are about 0.4-0.7 x l.l-1.4 microns, and the spore surface is smooth. No spiral formation, fungal hypha, sporangia and motile spores are observed.
  • Yeast 'starch agar medium (0.2% of yeast extract, 1.0% of soluble starch, 2.4% of string agar, pH7.0), 10 ° C, 20. C ⁇ 24 ° C, 27 ° C, 30. C ⁇ 37.
  • K929-43 ⁇ strain As a result of testing the growth of K929-43 ⁇ strain at each temperature of C, 45 ° C, and 50 ° C, it grows at any temperature except 45 ° (:, 50 ° C. The optimum growth temperature is 30. ° C.
  • Starch hydrolysis starch 'inorganic salt agar medium, ISP-medium 4, cultivation at 27 ° C
  • Starch hydrolysis was observed around 7 days after cultivation, and the effect was moderate.
  • D-glucose and inositol It grows on D-glucose and inositol, and probably uses D-fructose. L-arabinose, D-xylose, sucrose, raffinose, rhamnose and D-mannitol are not used.
  • Nitrate reduction reaction Peptone water containing 0.1% potassium nitrate, ISP-medium 8, culture at 27 ° C
  • the K929-43F1 strain elongates aerial hyphae which are relatively longer than the branched basal hyphae to form ring-shaped branches.
  • Mature spore chains are linked with 3 to 10 or more cylindrical spores, and the surface is smooth.
  • white-yellow ash aerial hyphae grow on the growth of light yellow to light yellow tea, and no soluble pigment is observed.
  • the optimum growth temperature is around 30 ° C.
  • Melanin-like pigment formation is positive on tryptone-yeast broth and peptone-yeast 'iron agar, and negative on tyrosine agar.
  • Starch has moderate water degradability and negative reaction for nitrate reduction.
  • the 2,6-diaminobimelic acid contained in the cell wall was L L-type.
  • the main menaquinone of the bacterial cell component is MK-9 (H6).
  • MK929-43F1 strain is considered to belong to the genus Streptomyces.
  • MK929-43F1 strain was submitted to the Institute of Biotechnology and Industrial Technology, Institute of Industrial Science and Technology, 1-3-1, Tsukuba-Higashi, Ibaraki, Japan, on September 21, 1999 under the accession number FEE P-17574. Was commissioned.
  • the MK929-43F1 strain received FE BP-7166 on the transfer date of May 19, 2000 under the terms of the Budapest Treaty to the aforementioned institute. It has been accepted by the deposit number.
  • the M929-43F1 strain was identified as Streptomyces' Sep eptoces sp.) At the present time, but this strain was identified as Streptomyces caespitosus (Streptomyces caespitosus literature International Journal oi Systematic (Bacteriology, Vol. 22, p. 281, 1972).
  • the form forms a ring branch.
  • the growth (base hypha) shows a characteristic yellow color.
  • the MK929-43F1 strain also produces the antibiotic mitomycin.
  • mygrass evening chin is produced by aerobically cultivating a mygrass evening chin-producing bacterium belonging to the genus Streptomyces in an appropriate medium.
  • Myglass evening tin can be produced.
  • the composition of the culture medium used can be any containing nutrient sources that can be used by Mygrass evening tin producing bacteria. Specifically, for example, glucose, galactose, glycerol, dextrin, sucrose, maltose, starch, oils and fats can be used as a carbon source.
  • organic substances such as soybean flour, cottonseed meal, dried yeast, yeast extract and colony liquor, and inorganic salts such as ammonium salts or nitrates such as ammonium sulfate, sodium nitrate and ammonium chloride are used.
  • inorganic salts such as calcium carbonate, sodium chloride, potassium chloride, phosphates, and heavy metal salts can be added.
  • a suitable antifoaming agent such as silicone oil can be added in a conventional manner.
  • the aerobic liquid culture method is the most suitable as in the commonly used method for producing antibiotics.
  • the culture temperature is suitably 20-30 ° C, but preferably 25-30 ° C.
  • the production of Mygrass-tin increases to a maximum in 5 days of culture in either the shaking culture method or the aeration stirring culture method.
  • Mygrass-tin from the culture or culture filtrate thus obtained.
  • Any suitable method can be used.
  • One of the methods is based on a method using the principle of extraction. Specifically, mygrass protein in a culture filtrate can be extracted with a water-immiscible solvent such as ethyl acetate.
  • Another method of harvesting mygrass sunset from the culture is based on the principle of adsorption, which is based on the already liquid form of mygrass sunsetin containing, for example, culture filtrate or Using the extract obtained by performing the above extraction operation, the target Mygrass resin is adsorbed using a suitable adsorbent, for example, silica gel, and then eluted with a suitable solvent to obtain Mygrass. You can get evening chin.
  • a suitable adsorbent for example, silica gel
  • the thus obtained Mygrass thickin solution is concentrated to dryness under reduced pressure to obtain a crudely purified Mygrass thickin solution.
  • the above-mentioned extraction method, adsorption method, gel filtration method and the like may be combined as necessary and the required number of times may be performed.
  • a crudely purified Mygrass resin is subjected to silica gel chromatography developed with a hexane-ethyl acetate system, and then subjected to a gel filtration method developed with a methanol system, whereby the Mygrass resin is purified. You can get pure chin products.
  • mygrass-tin is currently obtained by culturing microorganisms in the fourth method of the present invention, it can be produced by synthesis of related compounds, chemical modification, or all-synthetic chemistry. I can do it. It is also possible to use genetic engineering techniques. That is, it is also possible to incorporate the mygrass-tin-producing gene into an appropriate microorganism, for example, Escherichia coli, culture such a transformed microorganism, and obtain from the culture.
  • a strain belonging to the genus Streptomyces which is capable of producing mygrass sutin, is used. Specifically, it has been clarified by the present inventors that the Streptomyces sp.
  • Strain MK929-43F1 strain isolated by the present inventors is a mygrass-futin-producing bacterium, but it was used in the method of the present invention. As other possible strains, it is possible to isolate an appropriate mygrass-tin-producing bacterium from nature by a conventional method of isolating a useful substance-producing bacterium.
  • Mygrass dinner including Streptomyces sp MK929-43F1 strain
  • Mygrass evening tin by genetic techniques is also possible.
  • the fifth present invention provides, as a useful and novel microorganism, Streptomyces' SP MK929-43F1 strain or a mutant strain thereof having the property of producing mygrasstin.
  • This ⁇ 929-43 ⁇ strain has the mycological properties as described above, and has been registered with the aforementioned Institute of Biotechnology, Institute of Biotechnology, Industrial Science and Technology under FERM BP-7166 under the terms of the Budapest Convention. Deposited with the deposit number.
  • FIG. 1 of the attached drawings shows an infrared absorption spectrum of Mygrass.
  • Figure 2 of the attached drawing shows the proton nuclear magnetic resonance spectrum (500 MHz in heavy chloroform) of Mygrass.
  • Fig. 3 of the attached drawing shows the carbon-13 nuclear magnetic resonance spectrum of Mygrass Xintin (125 MHz in a double-mouthed form).
  • Streptomyces' Espiri MK929-43F1 strain (FERM P-17574) cultured on an agar slant medium was prepared by adding 2% dextrin, 1% glycerol, 1% sodium peptone, 0.3% yeast extract (Wako), 0.2% ammonium sulfate, 0.2% A liquid medium containing 0.2% calcium carbonate (adjusted to ⁇ 7.4) was dispensed in 100 ml aliquots into Erlenmeyer flasks (500 m volume) and inoculated into a medium sterilized at 120 ° C for 20 minutes by a conventional method.
  • the MK929-43F1 strain was subjected to rotary shaking culture at 27 ° C for 1 day in the medium.
  • a seed culture was obtained.
  • This seed culture was dispensed in 100 ml portions into a triangular flask (500 m volume) in the same liquid medium as used for seed culture, and sterilized at 120 ° C for 20 minutes by a conventional method.
  • the culture medium was inoculated in a volume of 2 ⁇ and cultivated by rotating and shaking at 27 ° C for 5 days.
  • the culture solution (5000 ml) thus obtained was filtered.
  • the obtained culture filtrate was extracted with an equal volume of ethyl acetate.
  • the ethyl acetate extract was concentrated under reduced pressure.
  • Product (1220 lmg) was adsorbed on a silica gel column (Merck Kieselgel (4 cm0xl5 cm)), and the active fraction eluted with chloroform-methanol (100: 1) was concentrated to dryness. Omg of crude product was obtained.
  • mygrass sutin obtained according to the present invention exhibits a growth inhibitory activity or a cancer cell killing activity of various human cancer cells, and exhibits a motility of cells, particularly human cancer cells. It has an inhibitory activity, and further inhibits the motility of human vascular endothelial cells and has an inhibitory activity on angiogenesis by inhibiting the ability to form a lumen. Therefore, mygrass protein is useful as an antitumor agent or an angiogenesis inhibitor.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Wood Science & Technology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Veterinary Medicine (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne la migrastatine, représentée par la formule (I), obtenue par culture d'une souche de Streptomyces sp. MK929-43F1. La migrastatine possède une activité antitumorale contre divers cancers humains ou contre des cellules tumorales, une activité d'inhibition de la motilité cellulaire, et une activité d'inhibition de l'angiogénèse sur les cellules endothéliales vasculaires.
PCT/JP2000/009147 1999-12-22 2000-12-22 Migrastatine, procede de production et compositions medicales correspondants WO2001046451A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24014/01A AU2401401A (en) 1999-12-22 2000-12-22 Migrastatin, process for producing the same and medicinal compositions

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JP36431699 1999-12-22
JP11/364316 1999-12-22

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WO2001046451A1 true WO2001046451A1 (fr) 2001-06-28

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006521407A (ja) * 2003-03-28 2006-09-21 スローン−ケッタリング・インスティテュート・フォー・キャンサー・リサーチ ミグラスタチンアナログおよびその使用
US8188141B2 (en) 2004-09-23 2012-05-29 Sloan-Kettering Institute For Cancer Research Isomigrastatin analogs in the treatment of cancer
US8957056B2 (en) 2004-05-25 2015-02-17 Sloan-Kettering Instiute For Cancer Research Migrastatin analogs in the treatment of cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0432697A2 (fr) * 1989-12-11 1991-06-19 Bristol-Myers Squibb Company Antibiotique BU-4146T
JPH07138257A (ja) * 1993-11-16 1995-05-30 Taisho Pharmaceut Co Ltd 骨吸収抑制物質ｂｒ−０４０及びｂｒ−０４２

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0432697A2 (fr) * 1989-12-11 1991-06-19 Bristol-Myers Squibb Company Antibiotique BU-4146T
JPH07138257A (ja) * 1993-11-16 1995-05-30 Taisho Pharmaceut Co Ltd 骨吸収抑制物質ｂｒ−０４０及びｂｒ−０４２

Non-Patent Citations (4)

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Title
JILL E. HOCHLOWSKI ET AL.: "Dorrigocins: novel antifungal antibiotics that change the morphology of ras-transformed NIH/3T3 cells to that of normal cells. II. Isolation and elucidation of structures", J. ANTIBIOT., vol. 47, no. 8, 1994, pages 870 - 874, XP002938947 *
KOICHI NAKAE ET AL.: "Migrastatin, a new inhibitor of tumor cell migration from streptomyces sp.MK929-43F1", J. ANTIBIOT., vol. 53, no. 10, 2000, pages 1130 - 1136, XP002938946 *
KOICHI NAKAE ET AL.: "Migrastatin, a novel 14-membered lactone from streptomyces sp.MK929-43F1", J. ANTIBIOT., vol. 53, no. 10, 2000, pages 1228 - 1230, XP002938945 *
KOKO SUGAWARA ET AL.: "Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity", J. ANTIBIOT., vol. 45, no. 9, 1992, pages 1433 - 1441, XP002938948 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006521407A (ja) * 2003-03-28 2006-09-21 スローン−ケッタリング・インスティテュート・フォー・キャンサー・リサーチ ミグラスタチンアナログおよびその使用
JP2006523233A (ja) * 2003-03-28 2006-10-12 コーネル・リサーチ・ファンデーション・インコーポレイテッド ミグラスタチンアナログ組成物およびその使用
US7943800B2 (en) 2003-03-28 2011-05-17 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
JP4719671B2 (ja) * 2003-03-28 2011-07-06 コーネル・リサーチ・ファンデーション・インコーポレイテッド ミグラスタチンアナログ組成物およびその使用
JP4928937B2 (ja) * 2003-03-28 2012-05-09 スローン−ケッタリング・インスティテュート・フォー・キャンサー・リサーチ ミグラスタチンアナログおよびその使用
US8202911B2 (en) 2003-03-28 2012-06-19 Cornell Research Foundation, Inc. Migrastatin analog compositions and uses thereof
US8324284B2 (en) 2003-03-28 2012-12-04 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
US8835693B2 (en) 2003-03-28 2014-09-16 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
US8957056B2 (en) 2004-05-25 2015-02-17 Sloan-Kettering Instiute For Cancer Research Migrastatin analogs in the treatment of cancer
US8188141B2 (en) 2004-09-23 2012-05-29 Sloan-Kettering Institute For Cancer Research Isomigrastatin analogs in the treatment of cancer

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