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WO2006101073A1 - Agent anti-cancereux et bacterie capable de produire un nouveau compose, la prunustatine - Google Patents

Agent anti-cancereux et bacterie capable de produire un nouveau compose, la prunustatine Download PDF

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Publication number
WO2006101073A1
WO2006101073A1 PCT/JP2006/305540 JP2006305540W WO2006101073A1 WO 2006101073 A1 WO2006101073 A1 WO 2006101073A1 JP 2006305540 W JP2006305540 W JP 2006305540W WO 2006101073 A1 WO2006101073 A1 WO 2006101073A1
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salt
grp78
expression
induction
chemical
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Japanese (ja)
Inventor
Toru Natsume
Kazuo Shinya
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National Institute of Advanced Industrial Science and Technology AIST
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National Institute of Advanced Industrial Science and Technology AIST
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    • 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
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/08—Oxygen as only ring hetero atoms containing a hetero ring of at least seven ring members, e.g. zearalenone, macrolide aglycons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • 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
    • 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 a novel compound "branastatin” that suppresses the expression of GRP78, a compound that suppresses the expression of GRP78 (neoantimycin analogs such as "SW163A”), an anticancer agent containing at least the compound,
  • the present invention relates to an actinomycete strain “Streptomyces violaceoniger 4521—SVS3 strain” capable of producing the compound.
  • the endoplasmic reticulum is one of the organelles of eukaryotes and performs protein synthesis, folding, sugar chain modification, and the like.
  • the state in which immature proteins accumulate in the endoplasmic reticulum is called ER stress.
  • ER stress For example, under stress conditions such as glucose starvation, protein folding is incomplete and immature proteins accumulate in the endoplasmic reticulum, resulting in endoplasmic reticulum stress.
  • a molecular chaperone refers to a protein that controls folding of a synthetic protein during protein synthesis.
  • Hsp60 Choperonin
  • Non-Patent Document 1 When endoplasmic reticulum stress is not eliminated by induction of molecular chaperone expression, a pathway leading to apoptosis (cell death) is activated (see Non-Patent Document 1).
  • Endoplasmic reticulum stress is known to be induced by compounds such as tunicamycin.
  • GRP78 Glucose-Regulated Protein 78—kD
  • HSPA5 Heat—Shoe k 70kD Protein 5
  • i BIP immunoglo Dulin heavv chain—Binding
  • Protein also called protein
  • a stress-responsive molecular chaperone belonging to the HSP70 family and present in the endoplasmic reticulum.
  • Solid tumors are generally known to have glucose-starved regions unlike normal tissues (see Non-Patent Document 3, etc.), and the expression of GRP78 is induced. It has been reported (see Non-Patent Document 4 etc.). In addition, it has been reported that GRP78 expression suppression suppresses apoptosis induction under glucose starvation conditions (see Non-Patent Document 5).
  • Neoantimycin analog is a compound represented by the following general formula:
  • SW163A is a compound of R force S methyl group
  • R is antisobutyl group
  • SW163B Is a compound having an R-catyl group and an R-force S-isopropyl group.
  • Neoantimycin is
  • R force S is an isopropyl group
  • R is an antibutyl group compound
  • SW-163A and SW-163B are substances identified from metabolites of the actinomycete “Streptomyces” genus, and although there are reports as immunosuppressants (Non-patent Document 10), they have specific actions. ⁇ The use is not reported. Neoantimycin is known for its chemical structure (see, for example, Non-Patent Document 11), but no specific action has been reported. The chemical structure of SW-163A is shown in [Chemical 4] below.
  • Patent Document 1 PCT / JP02 / 12237
  • Non-patent document 1 Biochemical Dictionary 3rd edition (Tokyo Kagaku Doujin): p422 (Gnore course regulatory protein), p607 (GRP94).
  • Non-Patent Document 2 Special Issue on Experimental Medicine, “Maturity / Developing Apoptosis Research”, Yodosha, 2004: p66-72 (apoptosis caused by endoplasmic reticulum stress)
  • Non-patent literature 3 om omida A et al, Drug resistance mediated by cellular stress response to the microenvironment of solid tumors Anticancer Drug Des (2): 169-77 (1999)
  • Non-patent literature 4 Jamora C, et al, 'Inhibition of tumor progression by suppression ofstr ess protein GRP78 / Bip induction in fibrosarcoma B / C10ME "Proc Natl Acad SciUS A. (15): 7690-4 (1996)
  • Non-Patent Document 5 Miyake H., et al 'Stress protein GRP78 prevents apoptosis induced b ycalcium ionophore, ionomycin, in human prostate cancer cells "J Cell Biochem. (3): 396-408 (2000)
  • Patent Document 6 Hae-Ryong Park, et al "Versipelostatin, a novel GRP78 / Bip molecula rchaperone down-regulator of microbial origin etrahedron Letters (43): 6941-6945 (2002)
  • Non-Patent Document 7 Park HR, et al "Effect on tumor cells of bloc ing survival response to glucose deprivation" J Natl Cancer Inst. (17): 1266- 7 (2004)
  • Non-Patent Document 8 Park HR., Et al Effect on tumor cells of blocking survival response to glucose deprivation "J Natl Cancer Inst (17): 1300-10 (2004)
  • Non-Patent Document 9 Lee AS., Et ai The glucose-regulated protein: stress induction and clinical application Trends Biochem Sci. (8): 504_10 (2001)
  • Non-Patent Document i3 ⁇ 4 0 Takahashi K., et al "Sw-163A and B, novel immunosuppressantspro prised by Streptomyces sp.” J Antibiot (11): 867_73 (2001)
  • Patent Document 11 Takeda Y., et al "Nuclear magnetic resonance and biosynthetic studies and structures elucidation of isoneoantimycin, a minormetabolite r elated to neoantimycin.” J Nat Prod (8): 978- 81 (1998)
  • a substance that suppresses induction of GRP78 expression in cancer cells may be effective as an anticancer agent.
  • the main object of the present invention is to search for a substance that suppresses the induction of GRP78 expression and to find a novel anticancer agent.
  • Antisobutyl group compound was named pranastatin A.
  • a novel compound, blanastatin represented by the following general formula [I ⁇ 1] Or a salt thereof, and a novel compound, blanastatin A represented by the following chemical formula [Dig 2], or a salt thereof.
  • the substituents R and R are
  • an isopropyl group (palin side chain structure) or an antibutyl group (leucine side chain structure) is particularly preferred.
  • the compound represented by the general formula [Chemical Formula 5] “Thin analog”. ) Has also been found to have an action of suppressing the expression of GRP78. Therefore, in the present invention, the neoantimycin analog represented by the following general formula [Chemical Formula 3] or a salt thereof, which suppresses the expression of GRP78, and the following chemical formula [i ⁇ 4] which suppresses the expression of GRP78.
  • the substituents R and R forces are methyl group (side chain structure of alanine) and isopropyl group (palin), respectively.
  • a substance that suppresses the induction of GRP78 expression in cancer cells may be effective as an anticancer agent. Therefore, a pharmaceutical composition containing at least one of the above-described compounds may be effective as an anticancer agent.
  • each of the above-mentioned compounds is, for example, Streptomyces violaceoniger 4521— SVS3 strain (Tsukuba Rinhito, Ibaraki Pref. It can be produced as a metabolite such as the deposit at the research institute and the Patent Biological Depositary, and the deposit number FERM BP-10548 (deposited March 3, 2006).
  • the compound according to the present invention since the compound according to the present invention is presumed to suppress the induction of GRP78 expression and induce apoptosis (cell death) of cancer cells, it may be effective as a pile cancer agent.
  • FIG. 1 is a graph showing that branastatin has an inhibitory effect on GRP78 expression induction.
  • FIG. 2 is a graph showing that SW_163A also has an inhibitory effect on GRP78 expression induction.
  • FIG. 3 A graph showing that branastatin has almost no effect on the induction of HSP70 expression.
  • FIG. 5 is a graph showing that branastatin force S induces apoptosis (cell death).
  • FIG. 6 Electron micrograph (low magnification) of Streptomyces violaceoniger 4521-3 ⁇ 33.
  • FIG. 7 Electron micrograph (high magnification) of Streptomyces violaceoniger 4521—SVS3 strain.
  • blanastatin A As an example of the blanastatin according to the present invention, the physical properties of blanastatin A are shown in Table 1.
  • Each data is data measured for branastatin A separated and purified by the following procedure. First, the cells were centrifuged from the culture solution (2 L) of Streptomyces violaceoniger 4521-SVS3 strain, and the cultured cells were extracted with acetone. Next, the acetone extract was concentrated, extracted twice with ethyl acetate, dehydrated with Na 2 SO, and then under reduced pressure.
  • [H] indicates specific rotation. “27” indicates the measurement temperature, and “D” indicates that the measurement was performed using the sodium D line. “C0.32” is the solution concentration and “CHC1” is measured in the mouthpiece form.
  • UV is the ultraviolet absorption spectrum
  • nm ( ⁇ ) is the maximum absorption
  • MeOH is the max.
  • Neoantimycin analogs SW-163A, SW-163B, neoantimycin
  • each compound according to the present invention includes salts, solvates and the like thereof.
  • salt for example, alkali metal salts (sodium salt, potassium salt, lithium salt, etc.) alkaline earth metal salts (calcium salt, magnesium salt, etc.), metal salts (aluminum salt, iron salt, zinc salt, copper salt, nickel salt, etc.) ), Inorganic salt (acetate, ammonium salt, etc.), organic amine salt (dibenzilamine salt, darcosamine salt, ethylenediamine salt, jetylamine salt, triethylamine salt, dicyclohexylamine salt, diethanolamine salt, tetramethylammonium salt, etc.) Amino acid salts (such as glycine salt, lysine salt, arginine salt, ornithine salt, and asparagine salt) can be applied.
  • alkali metal salts sodium salt, potassium salt, lithium salt, etc.
  • alkaline earth metal salts calcium salt, magnesium salt,
  • the pile cancer agent according to the present invention should contain at least the strength of branastatin (including their salts) or neoantimycin analog (including their salts) according to the present invention. It is not limited narrowly by the dosage form. Moreover, when a composition other than the compound according to the present invention is included, it is also included in the pile cancer agent according to the present invention.
  • the anticancer agent according to the present invention may be formulated into tablets, capsules, granules, powders, syrups, injections, and the like.
  • an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, a solubilizing agent, a suspending agent, a coating agent, and the like may be appropriately added. .
  • Planastatin and neoantimycin analogs can be produced using, for example, Streptomyces violaceoniger 4521-SVS3 strain of actinomycetes. This strain was deposited (Tsukuba Rinto, Ibaraki Pref. 1-1-1) Deposited at the National Institute of Advanced Industrial Science and Technology, the Patent Biological Depositary, located in the 6th central area, accession number FERM BP- 10548 March 3, 2018). The identification of this strain will be described later.
  • the strain can be cultured by the same method as that for ordinary actinomycetes (Strebtomyces). For example, the culture is performed at a culture temperature of 27 ° C (24-30 ° C) and aerobic conditions (shaking culture, aeration and agitation culture, etc.).
  • the main culture may be performed after first performing the culture for 2 to 3 days. Since the growth of the strain can be activated by pre-culturing with a small amount of medium, the efficiency of the culture should be improved by ingesting the medium into a large amount of medium after pre-culture. Can do.
  • the culture conditions such as culture temperature, aeration volume, and culture time can be changed as appropriate.
  • the bacterial cell components are separated, and the supernatant or filtrate is recovered.
  • Brunastatin can be purified by, for example, adsorption column chromatography using a carrier such as silica gel, gel filtration column chromatography using a gel filtration resin, ion exchange chromatography using anion exchange or cation exchange resin, HPLC. It can be performed by a method utilizing suppression of the expression activity of GRP78.
  • SW-163A can also be obtained, for example, by reducing pranastatin A using NaBH4 (sodium borohydride).
  • Example 1 is an experiment showing that branastatin according to the present invention has an inhibitory effect on GRP78 expression induction.
  • Luciferrase is an enzyme that catalyzes the oxidation reaction of the luminescent substance noreciferin. Luciferin is oxidized and colored by the action of luciferase.
  • a GRP78 promoter gene and a luciferase gene are inserted into a vector.
  • the luciferase gene is inserted downstream of the promoter.
  • the vector is introduced into cancer cells.
  • the candidate substance acts on the promoter site and expresses luciferase. Since the expressed luciferase oxidizes luciferin and develops color, the induction of GRP78 expression can be detected by detecting the color intensity.
  • HT1080G-L cells were used as cancer cells.
  • DG is the color intensity when 1-onM of 2-deoxyglucose is added to the cancer cells
  • PA is the color intensity when blanastatin A is added to the cancer cells. Represent each.
  • Deoxygnolecose is a gnorecose metabolism inhibitor and is found in cancer cells.
  • a compound that induces endoplasmic reticulum stress A compound that induces endoplasmic reticulum stress.
  • the pranastatin A-force cancer cell according to the present invention has an action of suppressing the expression induction of GRP78.
  • Example 2 is an experiment showing that the neoantimycin analog according to the present invention also has an inhibitory effect on GRP78 expression induction. The outline of the experiment is almost the same as in Example 1.
  • SW-163A also has an action of suppressing the induction of GRP78 expression.
  • Example 3 is an experiment in which it was investigated whether the blanastatin according to the present invention has an inhibitory effect on the induction of HSP70 expression.
  • HSP70 is a molecular chaperone belonging to the same family as GRP78, and it is known that expression is induced when heat shock (heat shock) is applied.
  • the vertical axis “Relative luciferase activity” indicates luciferase activity (detected color intensity). “None” is the color intensity when no heat shock is applied, “Heat shock” is the color intensity when heat shock is applied to the cancer cells, and “PA” is the addition of blanastatin A to the cancer cells In this case, the color intensity is shown respectively.
  • HSP70 expression was induced.
  • Example 4 is an experiment showing that pranastatin activity according to the present invention has an action to suppress GRP78 expression only under glucose starvation.
  • HeLa cells were cultured in DMEM medium.
  • pranastatin A was added to each medium at various concentrations, and 30 minutes later, 2-deoxyglucose or tunicamycin was added at each concentration, followed by incubation for 18 hours.
  • the top photo is a Western blot photo when 2_deoxygnosole is added
  • the bottom photo is a Western blot photo when Tsuyu-mycin is added.
  • 2_DG represents 2_deoxyglucose
  • Prunusutatin A represents pranastatin A
  • TM and “tsuyu-mycin”
  • each numerical value represents an added amount.
  • GRP78 indicates the position of the GRP78 band
  • actin indicates the position of the actin band.
  • the actin band is a control indicating that the number of collected cells is almost the same in each experimental condition.
  • the band of GRP78 was attenuated. In particular, in the lanes from the left to the fourth force, the band almost disappeared. This indicates that the induction of GRP78 expression was suppressed by brustatatin A supplementation.
  • branastatin A does not suppress the induction of GRP78 expression when GRP78 expression is induced by the addition of tsuyu forcemycin.
  • Example 5 is an experiment showing that the blanastatin according to the present invention induces apoptosis (cell death) as well as suppressing GRP78 expression induction.
  • Propidium iodide is one of the dyes that stain nucleic acids. It is a fluorescent dye that penetrates into dead cells and interacts with the DNA double helix in dead cells. Therefore, after supplying pranastatin A to cancer cells, we examined whether apoptosis occurred by staining dead cells with propidium iodide and counting the number of dead cells.
  • HT1080 cells (cancer cells) were treated with pranastatin A and tunicamycin or 2-deoxyglucose. Next, the cells were stained with propidium iodide. Next, the number of dead cells stained with propidium iodide was counted using an epifluorescence microscope.
  • the cell death rate markedly increased in the bar from the 12th to the rightmost from the left, compared to the bar from the 8th force ⁇ -th from the left.
  • Streptomyces violaceoniger 4521 Example of identification of SVS3 strain
  • This strain is an actinomycete isolated from soil collected in Kume-cho, Okiami Prefecture. Its morphological, cultural and physiological properties are as follows.
  • the electron micrographs of this strain are shown in Figs.
  • the aerial hyphae formed a long main axis, which was randomly branched.
  • a compact 3-6 rotation helical spore chain consisting of 10 or more was formed. No fragmentation of the basic mycelium was observed.
  • the spores were non-motile and were covered with a sheath at the beginning of the culture, and the morphology of the spores could not be discerned. However, after 3 weeks from the start of the culture, the spores protruded from the sheath and elliptical spores were observed. No sclerotia, sporangia, or other special forms were observed.
  • the cell wall chemical type was type (I) and contained LL-diaminopimelic acid.
  • the GC content of DNA is 73.2. /. Met.
  • Table 3 shows the culture properties.
  • the flora color of the village surface is gray, but it became damp after long-term culture.
  • the color of the reverse side was a light yellowish color S on inorganic salt starch agar, oatmeal agar, and tyrosin agar, and red to purple on other agars and did not change with pH. No formation of diffusible dye was observed
  • Melbiose + This strain has a spore chain form in which spores are long and spirally linked, and the cell wall chemical type is (I) type. Estimated to be a seed.
  • Example 7 shows an example of a method for culturing Streptomyces violaceoniger 4521-SVS3 strain.
  • the strain can be cultured in a large amount by culturing the strain according to the procedure described above, it is possible to obtain a culture solution containing the compound according to the present invention (branastatin, SW163, etc.) with high efficiency.
  • the blanastatin according to the present invention has applicability as an anticancer agent.
  • pranastatin suppresses the induction of GRP78 expression only in a glucose-starved state, it is assumed that pranastatin has little effect on the reaction system of cells other than cancer cells. Therefore
  • the pile cancer agent according to the present invention is likely to have higher safety with fewer side effects than conventional ones.

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Abstract

L'invention concerne la recherche d'une substance capable d'inhiber l'induction de l'expression de GRP78 afin de découvrir un nouvel agent anti-cancéreux. Pour ce faire, un nouveau composé représenté par la formule chimique 1 est, maintenant, établi comme substance capable d'inhiber l'induction de l'expression de GRP78 et appelée 'prunustatine'. Ladite prunustatine présente une structure identique à celle d'un composé connu SW-163A et elle peut être produite par une souche de Streptomyces Violaceoniger 4521-SVS3 ou similaire. Une composition pharmaceutique renfermant au moins le composé est probablement efficace en tant qu'agent anti-cancéreux.
PCT/JP2006/305540 2005-03-22 2006-03-20 Agent anti-cancereux et bacterie capable de produire un nouveau compose, la prunustatine Ceased WO2006101073A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108586571A (zh) * 2018-05-14 2018-09-28 上海交通大学医学院附属仁济医院 一种新抗霉素衍生物及其制备方法与应用
CN108611312A (zh) * 2018-05-14 2018-10-02 上海交通大学医学院附属仁济医院 新抗霉素生物合成途径酮基还原酶基因缺失菌株、构建方法及应用

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JPH11286486A (ja) * 1998-04-01 1999-10-19 Snow Brand Milk Prod Co Ltd 新規生理活性物質及びその製造法
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* Cited by examiner, † Cited by third party
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JPH11286486A (ja) * 1998-04-01 1999-10-19 Snow Brand Milk Prod Co Ltd 新規生理活性物質及びその製造法
WO2003044209A1 (fr) * 2001-11-22 2003-05-30 Toudai Tlo, Ltd. Nouveau derive d'acide tetronique

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Title
TAKAHASHI K. ET AL.: "SW-163A and B, Novel Immunosuppresants Produced by Streptomyces sp", THE JOURNAL OF ANTIBIOTICS, vol. 54, no. 11, 2001, pages 867 - 873, XP003006751 *
TAKEDA Y. ET AL.: "Nuclear Magnetic Resonance and Biosynthetic Studies of Neoantimycin and Structure Elucidation of Neoantimycin and Structure Elucidation of Isoneo-antimycin, a Minor Metabolite Related to Neoantimycin", J. NAT. PROD., vol. 61, 1998, pages 978 - 981, XP003006752 *
UMEDA Y. ET AL.: "Prunustatin A, a Novel GRP78 Molecular Chaperone Downregulator Isolated from Streptomyces violaceoniger", J. ANTIBIOT., vol. 58, no. 3, 2005, pages 206 - 209, XP009049105 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108586571A (zh) * 2018-05-14 2018-09-28 上海交通大学医学院附属仁济医院 一种新抗霉素衍生物及其制备方法与应用
CN108611312A (zh) * 2018-05-14 2018-10-02 上海交通大学医学院附属仁济医院 新抗霉素生物合成途径酮基还原酶基因缺失菌株、构建方法及应用
CN108586571B (zh) * 2018-05-14 2021-08-13 上海交通大学医学院附属仁济医院 一种新抗霉素衍生物及其制备方法与应用

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