WO2001053290A1 - Inhibiteurs de la division cellulaire et procede de production de ces inhibiteurs - Google Patents
Inhibiteurs de la division cellulaire et procede de production de ces inhibiteurs Download PDFInfo
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- WO2001053290A1 WO2001053290A1 PCT/JP2000/006807 JP0006807W WO0153290A1 WO 2001053290 A1 WO2001053290 A1 WO 2001053290A1 JP 0006807 W JP0006807 W JP 0006807W WO 0153290 A1 WO0153290 A1 WO 0153290A1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- 229960003048 vinblastine Drugs 0.000 description 1
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- 229960004528 vincristine Drugs 0.000 description 1
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Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
Definitions
- the present invention relates to a cell division inhibitor (cell cycle inhibitor), an antitumor agent, and a method for producing the same using an enzyme.
- the proliferation and differentiation of the cells that make up the human body are strictly controlled to maintain homeostasis.
- Cells divide and proliferate by rotating the cell cycle consisting of a series of processes: M phase, G 1 phase, S phase and G 2 phase. Abnormalities in the cell cycle control mechanism lead to cancer and immune diseases.
- the regulation mechanism of the cell cycle is being elucidated at the molecular level, and it is known that the substances that regulate the cell cycle may be antitumor agents and immunosuppressants.
- the role of tubulin, such as paclitaxel, vincristine, and vinblastine plays a central role in the accurate distribution of one of the cytoskeletal proteins, replicated during cell division, to daughter cells. Substances that inhibit steroids are attracting attention as antitumor agents or lead compounds of antitumor agents.
- An object of the present invention is to provide a cell division inhibitor having a stronger cell cycle inhibitory activity, particularly an antitumor activity, and a method for producing the same using an enzyme.
- the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, various dehydrodiketopiperazines and analogs thereof including dehydrophenylahistine have a stronger cell cycle inhibitory activity than (-)-phenylahistine. And found that the present invention was completed.
- the present invention includes the following inventions.
- X 1 and X 2 each independently represent an oxygen atom or a sulfur atom
- Y 3 represents an oxygen atom, a sulfur atom, —NR 3 — or one CR 31 R 32 —
- Y 4 represents an oxygen atom, a sulfur atom, —NR 4 — or _ CR 41 R 42 —
- R 10 is a halogen atom, (25 alkyl, C 2 - to Table 25 alkenyl group, C 2 _ 25 alkynyl group, (25 alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a ⁇ re Ichiru group, These groups may be substituted by other substituents, a part of the carbon chain may be branched, cyclic, or may contain a hetero atom,
- R M represents a halogen atom, (25 alkyl, C 2 _ 25 alkenyl, C 2 - to Table 25 alkynyl group, C, _ 25 alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a Ariru group, these May be substituted by another substituent, a part of the carbon chain may be branched, cyclic, may contain a hetero atom,
- R 3 and R 4 are each independently a hydrogen atom, a halogen atom, _ 25 alkyl, C 2 - 25 7 alkenyl group, C 2 _ 25 alkynyl group, an alkoxy group, Ararukiru group, a hydroxyl group, ⁇ amino group, a nitro Or an aryl group, and these groups may be substituted with other substituents, and a part of the carbon chain may be branched or cyclic, and may contain a hetero atom. May be
- R 31, R 32, R 41 and R 42 each independently are each independently a hydrogen atom, a halogen atom, an alkyl group, C 2 _ 25 alkenyl, C 2 - 25 alkynyl group, (25 alkoxy group, Ararukiru Represents a group, a hydroxyl group, an amino group, a nitro group or an aryl group; these groups may be substituted by other substituents; a part of the carbon chain may be branched or cyclic; It may contain a hetero atom,
- R 10 and R 3 , R 31 or any of R 32 may form a ring
- R 20 and R 4 may form a ring
- (B1) and (B2) each independently represent a carbon-carbon single bond or a carbon-carbon double bond, at least one of which is a carbon-carbon double bond, and the configuration thereof is either ⁇ or ⁇ . But
- At least one of the groups it may also have a decomposable protecting group in vivo les ⁇
- X, and chi 2 are both oxygen atoms
- Upsilon 3 and Upsilon 4 are both in one New .eta.
- R ID is a benzyl group
- (B1) and (B2) are both carbon-carbon double bonds
- R 2D is an isoptyl or benzyl group
- X, and X 2 Are both oxygen atoms
- Y 3 and Y 4 are Both are one NH—
- R IC is a benzyl group
- (B1) is a carbon-carbon single bond
- (B2) is a carbon-carbon Z—double bond
- R 2fl is the following formula (a ):
- the other substituent these groups May be substituted by a group, a part of the carbon chain may be branched or cyclic, and may include a hetero atom. May be one, or the same or different, may be a plurality of 5 or less, and may form a ring with each other,
- R 2 is a hydrogen atom, a halogen atom, (25 alkyl, C 2 _ 25 alkenyl, C 2 _ 25 Arukini Le group, C 25 alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a ⁇ Li Ichirumoto These groups may be substituted by other substituents, and a part of the carbon chain may be branched, cyclic, or may contain a hetero atom.
- R 3 and R 4 are each independently a hydrogen atom, a halogen atom, - 25 alkyl group, (2 _ 25 ⁇ alkenyl group, C 2 _ 25 alkynyl group, C 25 alkoxy group, Ararukiru group, a hydroxyl group, ⁇ Mino Group, nitro group or aryl group; these groups may be substituted by other substituents; a part of the carbon chain may be branched, cyclic, or heteroatom. May be included,
- R 5 is a hydrogen atom, a halogen atom, (25 alkyl, C 2 _ alkenyl, C 2 _ 25 Arukini group, (25 alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a ⁇ Li - Le group And these groups may be substituted with other substituents, and a part of the carbon chain may be branched, cyclic, or may contain a hetero atom.
- these groups may be substituted by other substituents, and a part of the carbon chain may be branched, cyclic, or may contain a hetero atom.
- R 7 and R 8 each independently represent a hydrogen atom, a halogen atom, (25 alkyl, C 2 - 25 ⁇ alkenyl group, C 2 _ 25 alkynyl group, (25 alkoxy group, Ararukiru group, a hydroxyl group, ⁇ amino group , A nitro group or an aryl group; these groups may be substituted by other substituents; a part of the carbon chain may be branched or cyclic; May be included,
- R 2 may form a ring
- R 6 , R 7 and R 8 may form a ring
- (B2) represents a carbon-carbon single bond or a carbon-carbon double bond
- At least one of the groups may have a protecting group that can be degraded in a living body.
- a cell division inhibitor comprising a compound represented by this E-form or a pharmaceutically acceptable salt thereof as an active ingredient.
- (9) A compound in which at least one of (B1) and (B2) in the formula (I) is a carbon-carbon single bond, or a compound in which (B2) in the formula (II) is a carbon-carbon single bond A dehydrogenase having an activity of converting the carbon-carbon single bond of a product into a carbon-carbon double bond.
- R is a hydrogen atom, a halogen atom, ( 25 alkyl group, C 2 -25 alkenyl group, C 2 -25 alkynyl group, ( ⁇ 25 alkoxy group, aralkyl group, hydroxyl group, amino group, nitro group or aryl) Represents a group, and these groups may be substituted by another substituent, a part of the carbon chain may be branched, cyclic, or may contain a hetero atom. One, or the same or different, a plurality of 5 or less may form a ring with each other,
- R 2 is a hydrogen atom, a halogen atom, C DOO 25 alkyl group, C 2 _ 25 alkenyl, C 2 - 25 Arukini group, an alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a ⁇ Li Ichiru group And these groups may be substituted by other substituents, and the — part of the carbon chain may be branched, cyclic, or may contain a hetero atom,
- R 3 and R 4 are each independently a hydrogen atom, a halogen atom, _ 25 alkyl group, Ji 2 _ 25 ⁇ alkenyl group, C 2 _ 25 alkynyl group, (25 alkoxy group, Ararukiru group, a hydroxyl group, ⁇ amino group , A nitro group or an aryl group; these groups may be substituted by other substituents; a part of the carbon chain may be branched or cyclic; May be included,
- R 5 is a hydrogen atom, a halogen atom, (25 alkyl, C 2 _ 25 alkenyl, C M5 Arukini group, (: Bok 25 alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a ⁇ Li Ichirumoto These groups may be substituted by other substituents, and a part of the carbon chain may be branched, cyclic, or may contain a hetero atom.
- R 6 is a hydrogen atom, a halogen atom, an alkyl group, C 2 - 25 alkenyl group, (25 Arukini group, - 25 alkoxy group, Ararukiru group, a hydroxyl group, an amino group, a nitro group or a ⁇ Li And these groups may be substituted by other substituents, and the — part of the carbon chain may be branched, cyclic, or may contain a hetero atom.
- R 7 and R 8 each independently represent a hydrogen atom, a halogen atom, (25 alkyl, C 2 _ 25 7 alkenyl group, C 2 _ 25 alkynyl group, (25 alkoxy group, Ararukiru group, a hydroxyl group, ⁇ amino group , A nitro group or an aryl group; these groups may be substituted by other substituents; a part of the carbon chain may be branched or cyclic; May be included,
- R 2 and R 3 may form a ring
- R 4 and R 5 , R 6 , R 7 and may form a ring
- (B2) represents a carbon-carbon single bond or a carbon-carbon double bond
- At least one of the groups may have a protecting group that can be degraded in a living body.
- halogen atom means fluorine, chlorine, bromine or iodine unless otherwise specified.
- the C, -25 alkyl group represented by R 41 or R 42 is an alkyl group having 1 to 25 carbon atoms, and may be any of linear, branched or cyclic, such as methyl , Ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, 5-methylhexyl, cycloheptyl, octyl, 6-methylheptyl , Nonyl, 7-methyloctyl, decyl, and 8-methylnonyl, and is preferably (,. Alkyl, more preferably (6 alkyl.) These alkyl groups may be substituted with other substituents. And may contain hetero atoms such as halogen, oxygen
- alkenyl group having from 2 to 25 atoms which may be linear, branched or May be any of cyclic groups such as vinyl, propenyl, 1,1-dimethyl-2-provenyl and 3-methyl-3-butenyl groups, and is preferably C 2 -1 () alkenyl. Yes, even more preferably from _ 6 Arukeniru.
- These alkenyl groups may be substituted with other substituents, and may contain a hetero atom such as halogen, oxygen, sulfur, or nitrogen.
- R !, R 2, R 3, 4, R 5, R 6, R 7, R 8, ⁇ 10, 20, 31, 32, JV 4i also [or lambda 42 Table ⁇ Re C 2 - 25 Bruno 'Rukiniru group Is an alkynyl group having 2 to 25 carbon atoms, which may be linear, branched or cyclic, such as ethynyl, propynyl, and butynyl, preferably C 2 D alkynyl, and more preferably Is C 2 _ 6 alkynyl. These alkynyl groups may be substituted by other substituents, and may contain a hetero atom such as halogen, oxygen, sulfur, or nitrogen.
- a hetero atom such as halogen, oxygen, sulfur, or nitrogen.
- the C-tozo'-alkoxy group is an alkoxy group having 1 to 25 carbon atoms, and may be linear, branched or cyclic.
- the aryl group represented by R 20 , R 31 , R 32 , I ⁇ or R 42 is a monocyclic or polycyclic aromatic hydrocarbon group, such as phenyl, naphthyl, and anthranyl. It is phenyl.
- These Ariru groups other substituents e.g., (- Bok 6 alkyl (preferably methyl, Echiru, propyl), ⁇ alkoxy, halogen, nitro, Amino, carboxyl, hydroxy -; alkyl Le, hydroxy, protected hydroxy It may be substituted, and may contain a hetero atom such as oxygen, sulfur, or nitrogen as a ring member.
- Araru Kill group represented by R 3, R 41 or R 42, the Ariru a C M alkyl substituted with a group such as benzyl, phenethyl, naphthylmethyl, it includes anthranilamide methyl, preferably benzyl is there.
- Ararukiru groups other substituents, such as alkyl (preferably rather is methyl, Echiru, propyl), CI_ 6 alkoxy, halogen, nitro, Amino, Karupokishiru, hydroxy-(6 alkyl, hydroxy, substituted by protected hydroxy And may contain a hetero atom such as oxygen, sulfur, or nitrogen as a ring member.
- R have R 2, R 3,, R 5, R 6, R 7, R 8, R 1G, R 2.
- R 32, R 41 or R 42 for example, alkyl, - 6 alkoxy, halogen, Karupokishiru, hydroxy - alkyl, hydroxy, and a protected hydroxy.
- R 1Q may form a ring with any of R 3 , R 3I , and I ⁇
- R 2U may form a ring with any of R 4 , R 4I and] ⁇
- R 2 and R 3 may form a ring
- R 4 and R 5 , R 6 , R 7 and R 8 may form a ring It may be.
- a methyl-3-butenyl group and a alkenyl group corresponding to these isoprene units are preferably a plurality, preferably up to three units (up to 15 carbon atoms) bonded together.
- the substituents in the above formulas (I) and (II) may have a protecting group that can be degraded in a living body.
- protecting groups for example, as the protecting group for the amino group, specifically, “Development of Pharmaceuticals”, Vol. 13, “Drug Delivery Method” (edited by Hitoshi Takasaki, Hirokawa Shoten, Heisei (July 1975) Protecting groups having a binding mode such as acid amides and carbamates as described in Table 2.29 on page 16 may be used, and acetyl groups derived from fatty acids such as acetyl groups. Is preferred.
- the double bond of the compound represented by the formula (I) or (II) may be in either Z configuration or E configuration, but is preferably in Z configuration.
- (Bl) and Z or (B2) are a carbon-carbon double bond
- the substituent bonded to the carbon-carbon double bond is a corresponding divalent group.
- a methyl group is a methylene group
- a benzyl group is a phenylmethylene (benzylidene) group.
- X and X 2 are both oxygen atoms
- Y 3 and Y 4 are both ⁇ —
- R 1 () is a benzyl group
- (B 1) And (B2) are both carbon-carbon double bonds
- R 2fl is an isobutyl group
- arponorsine compound name: 3- (Z) -benzylidene-6- (Z) -isobutylidene — 2, 5—piperazinedione
- X and X 2 are both oxygen atoms; Y 3 and Y 4 are both NH—; Is a benzyl group, (B1) is a carbon-carbon single bond, ( ⁇ 2) is a carbon-carbon ⁇ -double bond, and is the following formula (a):
- (B1) is a carbon-carbon single bond
- (B2) is a carbon-carbon Z-double bond
- R 2D is a substituted or unsubstituted imidazole-4- Those other than the compound which is dimethylene are used.
- (B1) is preferably a carbon-carbon double bond
- (B2) is preferably a carbon-carbon single bond or a carbon-carbon double bond
- (B1) and (B2) Are both preferably carbon-carbon double bonds.
- Preferred examples of the compound represented by the formula (I) or (II) include 3- (imidazole-14-ylmethylene) -16- (phenylmethylene) pidazine-12,5-dione, 3-[(5 —Methylimidazole—41yl) methylene] —6— (phenylmethylene) piperazine-1,2,5-dione,
- the pharmaceutically acceptable salt of the compound represented by the formula (I) or ( ⁇ ) is a common organic or inorganic non-toxic salt, and when the compound is a basic substance, it is preferable. Is used as a hydrochloride, hydrobromide, sulfate, nitrate, acetate, methanesulfonic acid, or toluenesulfonic acid salt. When the compound is an acidic substance, it is preferably used with an inorganic base. It is used as a salt, for example, an alkali metal salt (for example, sodium salt, potassium salt, etc.) or an alkaline earth metal salt (for example, calcium salt, magnesium salt, etc.). As used herein, "pharmaceutically acceptable” means acceptable in the field of pharmaceuticals, veterinary medicine, pesticides, fungicides, insecticides, etc., as well as research reagents. It is.
- the cell division inhibitor of the present invention can be used for the purpose of inhibiting prokaryotic or eukaryotic cell division, cell cycle and female nucleus male-nucleus fusion. Specifically, it is useful as a fungicide, agrochemical, veterinary medicine, insecticide, pharmaceutical, and research reagent. Furthermore, it is particularly useful as an antitumor agent in pharmaceuticals.
- the cell division inhibitor of the present invention is effective for a disease state in which cell division is repeated randomly. It is particularly useful for cancer, and is also useful for certain autoimmune diseases, and pathological conditions in which certain cells such as rheumatoid arthritis have continued to proliferate in a disordered manner.
- the antitumor agent of the present invention may contain, if necessary, other pharmaceutically active ingredients, for example, other antitumor agents, in addition to the active ingredient.
- other pharmaceutically active ingredients for example, other antitumor agents
- the active ingredient in an amount of 5 to 80% by weight.
- the active ingredient is preferably contained at a ratio of 1 to 30% by weight.
- the active ingredient is preferably contained at a ratio of 1 to 10% by weight.
- the dosage can be adjusted as appropriate according to the patient's age, weight, condition, and the like.
- the above-mentioned antitumor agent of the present invention can be administered once a day, but it can also be administered in two or three doses at appropriate intervals.
- the administration can be performed once to three times a day by injection, or once every two to three days, or by continuous administration such as infusion.
- the dehydrogenase of the present invention is a compound wherein at least one of (B1) and (B2) in the formula (I) is a carbon-carbon single bond, or (B2) in the formula (II) is a carbon-carbon single bond.
- a compound that is a bond can be used as a substrate, preferably, the compound represented by the formula
- X and X 2 are both oxygen atoms, and Y 3 and Y 4 are both —NH—
- the compound is used as a substrate, and a cyclic dipeptide in which two L-amino acids are condensed to form a diketopiperazine ring or a substituted product thereof is particularly preferably used as a substrate.
- the amino acids to be condensed preferably include cyclic (aromatic) amino acids such as phenylalanine, histidine, tryptophan, and cysteine.
- Examples of the substituent in the cyclic dipeptide substituent include a halogen atom, ( 25 alkyl group, C 2 -25 alkenyl group, C 2 ⁇ alkynyl group, Ci_ 25 alkoxy group, aralkyl group, hydroxyl group, amino group, nitro group, And these groups may be substituted with other substituents, and the carbon chain may be partially branched, cyclic, or contain a hetero atom. And may form a ring with each other, and may have a protecting group which can be decomposed in a living body, preferably an alkyl or alkenyl group having 2 to 6 carbon atoms, more preferably 1,1-dimethyl dimethyl group. A 2-propenyl group.
- the dehydrogenase of the present invention has various molecular weights, but preferably has a molecular weight of 700 kDa to 800 kDa.
- the dehydrogenase of the present invention comprises nicotine adenine dinucleotide (NAD), nicotine adenine dinucleotide phosphate (NADP), flavin adenine dinucleotide (FAD), flavin mononucleotide (FII), and pyroquinoline as coenzymes.
- NAD nicotine adenine dinucleotide
- NADP nicotine adenine dinucleotide phosphate
- FAD flavin adenine dinucleotide
- FII flavin mononucleotide
- pyroquinoline as coenzymes.
- synthetic compounds such as dichlorophenol indophenol (DCIP), phenazine methosulfate (PMS), ferricyanide, tetramethylphenylene diamine, quinones, etc. FMN, PQQ, cytochromes, DCIP, PMS, ferricyanide, tetramethylphenylenediamine And quino
- the dehydrogenase of the present invention may be obtained from any organism, but is preferably derived from microorganisms such as bacteria, actinomycetes and filamentous fungi, more preferably from actinomycetes,
- Dehydrogenase from Streptomyces albulus has the following physicochemical properties
- the form of use of the dehydrogenase of the present invention may be a tissue or a cell, a cell-free extract, or an enzyme solution obtained by partially or completely purifying the extract.
- the purification method may be a general enzyme purification method. Also, a multi-step reaction may be performed at once by mixing other enzymes.
- a compound in which at least one of (B1) and (B2) in the formula (I) is a carbon-carbon single bond, or (B2) in the formula (II) is Using a compound having a carbon-carbon single bond as a substrate, a compound wherein at least one of (B1) and (B2) in the formula (I) is a carbon-carbon double bond, or ( Compounds in which B2) is a carbon-carbon double bond can be produced, and these are useful as cell division inhibitors or antitumor agents.
- the active ingredient of the cell division inhibitor of the present invention comprises a small amount of (B1) and (B2) in the above formula (I). At least one of them is a carbon-carbon double bond.
- Actinomycetes for example Streptomyces albulus K023 strain (National Inst iute Biotechnology and Human-Technology Agency of Industrial Technology Institute of the Ministry of International Trade and Industry of 1-3-1 Higashi, Tsukuba, Ibaraki, Japan Science and Technology) and deposited under the accession number FERM BP-6994 on January 14, 2012.) is cultured, and a dehydrogenase is prepared from the culture and allowed to act on fenilahistin.
- the method for collecting the novel compound dehydrophenylahistin is specifically described in Examples below, but the enzyme may be purified and used, or the cell extract may be used as it is.
- the preparation of the dehydrogenase can be carried out generally according to the method of culturing actinomycetes belonging to the genus Streptomyces.
- a means generally used for purifying an enzyme derived from a microorganism is appropriately used.
- a method of performing a dehydrogenation reaction using the enzyme solution or the bacterial cell extract prepared as described above is specifically described in Examples described later.
- the reaction is performed by mixing the solution and its substrate, phenylahistine. If necessary, an organic solvent can be added to the reaction solution.
- an organic Means usually used for compound isolation and purification can be appropriately used.
- various ion exchange resins, non-ionic adsorption resins, gel filtration chromatography, or chromatography using adsorbents such as activated carbon, alumina, silica gel and high-performance liquid chromatography, or crystallization, concentration under reduced pressure, freeze drying, etc. can be used alone or in appropriate combination, or can be used repeatedly.
- the dehydrophenylahistin produced as described above has a cell division inhibitory activity as shown in the Examples described later.
- the method of use, dosage form, and dosage (use amount) of the cell division inhibitor of the present invention containing dehydrophenylahistine as an active ingredient are appropriately determined according to the purpose of use.
- the administration form may be oral or parenteral.
- the dosage form include oral administration agents such as tablets, powders, capsules, granules, extracts and syrups, and parenteral administration agents such as injections or suppositories.
- the preparations are manufactured by a known method using pharmaceutically acceptable additives such as excipients and binders.
- the clinical dose of the antitumor agent containing dehydrophenylahistine as an active ingredient varies depending on the patient's age, body weight, sensitivity, and the degree of symptoms.
- the dose is about 0.1 ing to 1 g per day, and it can be administered once or several times a day. If necessary, an amount outside the above range can be used.
- the effective use range of the above-mentioned cell division inhibitor containing dehydrophenylahistine as an active ingredient is 0.01 to 100 g / mL, but the appropriate use amount depends on the type of cultured cell line and the purpose of use. It depends on the target. If necessary, an amount outside the above range can be used.
- a 2 amino acid two are represented cyclic di-peptides) to form a diketopiperazine ring fused respectively
- a 2 are amino acid 1 letter code) and indicates all LL body unless specialized reporting
- the D-form is denoted as etc. as necessary.
- the dehydro form is represented by ⁇ , CAAiA 2 is cycloiAA, -A 2 ), CA AA 2 represents cyclo (AA r AA 2 ), ⁇ CA, A 2 «CAA, A 2 ⁇ CA, ⁇ 2 and a mixture of CAA, ⁇ 2 .
- PLH indicates phenylahistine.
- Solid medium consisting of glucose 0.5%, glycerin 2%, yeast extract 0.2%, pharma media (cotton seeds) 2%, sodium chloride 0.25% and agar 1.5% (H 6.5) (20 mL in a 9 cm diameter petri dish)
- the culture medium contains phenylahistine-producing bacteria (Aspergillus ustus NSC-F038 strain, 1-3-1 Tsukuba-Higashi, Ibaraki, Japan, National Institute of Biotechnology and Industrial Technology)
- Table 2 shows the culture conditions.
- Antifoaming agent (Antiiorm AFI emulsion) 10 g / 3 L
- the culture solution (40 mL) was centrifuged (20, '000Xg, 15 min, 4 V) to obtain bacterial cells.
- the cells were suspended in 40 mL of physiological saline, and centrifuged again (20, OOOXg, 15 min, 4 ° C) to wash the cells.
- the cells were suspended in 7.3 l of sodium phosphate buffer (10 mM, H 8.0) and sonicated (1.5 min, KUBOTA INS0NAT0R 201M).
- the supernatant obtained by centrifuging this solution (20, OOOXg, 15 min, 4) was used as a cell-free extract.
- Table 3 shows the composition of the reaction solution.
- reaction solution 100 mL of the reaction solution was dispensed into 200 mL Erlenmeyer flasks in 20 mL portions, and the reaction was performed at 160 strokes / minute for 24 hours. After the reaction, a yellow precipitate was obtained by centrifugation (20, OOOXg, 15 min, 4 V). This precipitate was dissolved in 55 mL of methanol, and centrifuged again (20, OOOXg, 15 min, 4 V.). The obtained supernatant was dried under reduced pressure and recrystallized from methanol to obtain 5.58 mg of yellow needle crystals of dehydrophenylahistine.
- reaction solution 100 mL of a reaction solution having the composition shown in Table 4 was prepared, dispensed into five 20 mL Erlenmeyer flasks, and subjected to a reciprocal reaction (160 strokes / rain) at 50 for 24 hours. After 24 hours, the reaction solution was centrifuged (4 ° C, 20,000 Xg, 15 minutes) to obtain a supernatant.
- the supernatant was extracted with ethyl acetate and purified by high performance liquid chromatography (Purification conditions: Waters 600 Controller, 486 Tunable Absorbance Detector, 616 Pump, column Inertsil 0DS-3 Diameter 20 face X250, solvent 60% methanol, flow rate 10 mL) / min, detection UV 256 nm), and three types of dehydro-forms were obtained with retention times of 3.9 minutes, 9.1 minutes, and 1 L for 6 minutes.
- CE-AFAH E-tetradehydro form
- C-AFAH Z-tetrade hydro form
- CFAH dehydro form
- various diketopiperazines as substrates and performing a dehydrogenation reaction using the enzyme of the present invention, various diketopiperazine aldehydes were produced as follows.
- the reaction was carried out at 37 ° C using a reaction solution having the composition shown in Table 5.
- the reaction product was analyzed by HPLC, and the product was detected by UV absorption (256 nm).
- the dehydro form obtained by the present method is shown below.
- various diketopiperazines as substrates and performing a dehydrogenation reaction using the enzyme of the present invention, various diketopiperazine aldehydes were produced as follows.
- the reaction was carried out at 37 using a reaction solution having the composition shown in Table 6.
- the reaction products were analyzed by HPLC, and the products were detected with a photodiode array detector (multiwavelength UV, 220 dishes to 400 MI).
- the dehydro form obtained by the present method is shown below.
- (OMe) in the name of the substance indicates that the olepoxyl group in the side chain (r-position) of aspartic acid is methylated
- D (OEt) indicates the carboxyl of the side chain (ascending position) of aspartic acid. It shows that the group is ethylated.
- various diketopiperazines as a substrate and performing a dehydrogenation reaction using the enzyme of the present invention, various diketopiperazine dehydro bodies were produced as follows.
- the reaction was performed in the same manner as in Example 3, and the amount of enzyme reaction was determined by measuring the change in absorbance at 600 mil caused by the coenzyme.
- Table 7 shows the enzyme reaction amount (absorbance change, relative to CFL of 100) for each substrate.
- the St. reptomyces albulus K023 strain was cultured using a mini jar, 167.12 g of cells were obtained using 3 L of medium, and a cell-free extract was prepared as follows.
- the buffer used was 10 iiiM sodium phosphate buffer (pH 8.0), and 0.1 mM of DTT was added.
- MonoQ active fraction (225 L concentrated)
- the buffer used was 10 mM sodium phosphate buffer (pH 8.0), and DTT (0.1 mM) and NaCl (0.3 M) were added.
- Table 11 shows the activity in each fraction.
- the most active fractions 13-16 were pooled and concentrated by ultrafiltration.
- the active fraction was further subjected to gel filtration chromatography (TSK G3000SWXL) using Waters LC Module as follows.
- the buffer used was 100 mM sodium phosphate buffer (pH 7.5).
- Enzyme reactions were carried out using various diketobiperazines as substrates and using the enzyme of the present invention in the reaction solution composition shown in Table 14. Obtained for the enzyme reaction, KoTsuta c measuring method embryo mitotic inhibitory activity measuring test Sanshowu two remain in the reaction solution without purifying the reaction product, The Journal of Ant ibiot ics, Vol. 52, p The method described in 1017, 1999 was followed. However, because the timing of the first cleavage differs depending on the type of ⁇ , the inhibition of cleavage was observed 1 hour after fertilization in the present test using S. niger. Since the reaction product was not purified, the concentration of the inhibitor was based on the concentration of the substrate added to the enzyme reaction system. Table 15 shows the results of the test for measuring the embryo division inhibition activity of Salamander ii with the maximum concentration of 25 / g / mL corresponding to the substrate concentration.
- cleavage inhibition activity (cell division inhibitory activity) was measured for Pahunji, Hasunohakashipan and Salamander, respectively. The measuring method followed the method described in The Journal of Antibiotics, Vol. 52, P. 1017, 1999. However, since the timing of the first cleavage varies depending on the type of ⁇ , four hours after fertilization in the test using Bahunduni and Hasunohakashi bread, and one hour after fertilization in the test using Sansho-uni. Inhibition was observed. Table 16 shows the results.
- Dehydropheni for cell division The MIC for all cells was 0.0061 / ig / mL, and the MIC for cell division of Bahun ⁇ was 0.00038 At g / mL, which was lower than that of undehydrogenated (-)-phenylahistine. It exhibited a 50-fold to 1000-fold inhibitory activity.
- (Z, Z) -tetradehydro-CFH obtained by dehydrogenation of CFH showed an inhibitory activity 15 times or more that of CFH.
- dehydrodiketopiperazines and (Z, Z) -tetrahydrohydro-CFH and various other dehydrodiketopiperazines showed cell division inhibitory effects. Have been shown to be useful as cytostatic and antitumor agents.
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Priority Applications (13)
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BRPI0017067A BRPI0017067B8 (pt) | 2000-01-18 | 2000-09-29 | inibidor de divisão de célula, desidrogenase, método para a produção de um inibidor de divisão de célula e composto |
IL15043000A IL150430A0 (en) | 2000-01-18 | 2000-09-29 | Cell division inhibitors and process for producing the same |
NZ519989A NZ519989A (en) | 2000-01-18 | 2000-09-29 | Cell division inhibitors and process for producing the same |
CA2403790A CA2403790C (en) | 2000-01-18 | 2000-09-29 | A cell division inhibitor and a production method thereof |
JP2001553764A JP4810043B2 (ja) | 2000-01-18 | 2000-09-29 | 細胞分裂阻害剤及びその製造方法 |
AU74511/00A AU782917C (en) | 2000-01-18 | 2000-09-29 | Cell division inhibitors and process for producing the same |
EP00963011A EP1264831A4 (en) | 2000-01-18 | 2000-09-29 | Cell division inhibitors and a method for fixing the same |
MXPA02006826A MXPA02006826A (es) | 2000-01-18 | 2000-09-29 | Un inhibidor de division celular y un metodo de produccion del mismo. |
BR0017067-4A BR0017067A (pt) | 2000-01-18 | 2000-09-29 | Inibidor de divisão de célula, desidrogenase, método para a produção de um inibidor de divisão de célula e composto |
US10/181,786 US6972289B1 (en) | 2000-01-18 | 2000-09-29 | Cell division inhibitor and a production method thereof |
IL150430A IL150430A (en) | 2000-01-18 | 2002-06-26 | Cell division inhibitors |
US11/281,773 US20060079534A1 (en) | 2000-01-18 | 2005-11-17 | Cell division inhibitor and a production method thereof |
AU2005242133A AU2005242133B2 (en) | 2000-01-18 | 2005-12-07 | Cell division inhibitors and process for producing the same |
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US (2) | US6972289B1 (ja) |
EP (1) | EP1264831A4 (ja) |
JP (1) | JP4810043B2 (ja) |
KR (1) | KR100831400B1 (ja) |
AU (2) | AU782917C (ja) |
BR (2) | BR0017067A (ja) |
CA (1) | CA2403790C (ja) |
IL (2) | IL150430A0 (ja) |
MX (1) | MXPA02006826A (ja) |
NZ (1) | NZ519989A (ja) |
WO (1) | WO2001053290A1 (ja) |
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US8247552B2 (en) | 2002-08-02 | 2012-08-21 | Nereus Pharmaceuticals, Inc. | Analogs of dehydrophenylahistins and their therapeutic use |
JP2006511534A (ja) * | 2002-08-02 | 2006-04-06 | ネレアス ファーマシューティカルズ インコーポレイテッド | デヒドロフェニラヒスチンおよびそれらの類似体、ならびにデヒドロフェニラヒスチンおよびそれらの類似体の合成 |
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US7956058B2 (en) | 2002-08-02 | 2011-06-07 | Nereus Pharmaceuticals, Inc. | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof |
US7935704B2 (en) | 2003-08-01 | 2011-05-03 | Nereus Pharmaceuticals, Inc. | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof |
JP2007520565A (ja) * | 2004-02-04 | 2007-07-26 | ネレアス ファーマシューティカルズ インコーポレイテッド | デヒドロフェニラヒスチン及びそれらの類似体、並びにデヒドロフェニラヒスチン及びそれらの類似体の合成 |
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Also Published As
Publication number | Publication date |
---|---|
AU782917C (en) | 2006-11-23 |
AU7451100A (en) | 2001-07-31 |
US6972289B1 (en) | 2005-12-06 |
AU2005242133B2 (en) | 2009-09-03 |
NZ519989A (en) | 2004-05-28 |
BRPI0017067B1 (pt) | 2019-08-27 |
IL150430A0 (en) | 2002-12-01 |
IL150430A (en) | 2011-03-31 |
AU2005242133A1 (en) | 2006-01-05 |
KR100831400B1 (ko) | 2008-05-21 |
CA2403790A1 (en) | 2001-07-26 |
US20060079534A1 (en) | 2006-04-13 |
ZA200206576B (en) | 2003-05-12 |
BR0017067A (pt) | 2002-10-22 |
JP4810043B2 (ja) | 2011-11-09 |
EP1264831A4 (en) | 2005-11-23 |
CA2403790C (en) | 2011-09-27 |
KR20020082484A (ko) | 2002-10-31 |
MXPA02006826A (es) | 2004-04-05 |
AU782917B2 (en) | 2005-09-08 |
EP1264831A1 (en) | 2002-12-11 |
BRPI0017067B8 (pt) | 2021-05-25 |
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