TW201034681A - Process for the preparation of lactic- and phenyllactic-acid-containing, optically active, cyclic depsipeptides with 24 ring atoms with the aid of fungal strains of Rosellinia species and further Xylariaceae - Google Patents
Process for the preparation of lactic- and phenyllactic-acid-containing, optically active, cyclic depsipeptides with 24 ring atoms with the aid of fungal strains of Rosellinia species and further Xylariaceae Download PDFInfo
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- TW201034681A TW201034681A TW098143185A TW98143185A TW201034681A TW 201034681 A TW201034681 A TW 201034681A TW 098143185 A TW098143185 A TW 098143185A TW 98143185 A TW98143185 A TW 98143185A TW 201034681 A TW201034681 A TW 201034681A
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- 230000002538 fungal effect Effects 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 16
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 15
- NWCHELUCVWSRRS-SECBINFHSA-N (2r)-2-hydroxy-2-phenylpropanoic acid Chemical compound OC(=O)[C@@](O)(C)C1=CC=CC=C1 NWCHELUCVWSRRS-SECBINFHSA-N 0.000 title claims abstract description 11
- 108010002156 Depsipeptides Proteins 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000006413 ring segment Chemical group 0.000 title claims abstract description 11
- 241001299709 Rosellinia Species 0.000 title claims abstract 7
- 241001523964 Xylariaceae Species 0.000 title claims abstract 7
- 108010004210 PF 1022A Proteins 0.000 claims abstract description 19
- YJNUXGPXJFAUQJ-LYWANRAQSA-N PF1022A Chemical compound C([C@@H]1C(=O)N(C)[C@H](C(O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](CC=2C=CC=CC=2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O1)=O)CC(C)C)C1=CC=CC=C1 YJNUXGPXJFAUQJ-LYWANRAQSA-N 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 8
- 244000079386 endoparasite Species 0.000 claims abstract description 6
- 230000002255 enzymatic effect Effects 0.000 claims abstract 2
- 239000002023 wood Substances 0.000 claims description 12
- 241000233866 Fungi Species 0.000 claims description 10
- 239000003610 charcoal Substances 0.000 claims description 10
- 241000894006 Bacteria Species 0.000 claims description 8
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- 239000004310 lactic acid Substances 0.000 claims description 5
- 241000233614 Phytophthora Species 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 3
- 229920002101 Chitin Polymers 0.000 claims 2
- 102000004190 Enzymes Human genes 0.000 claims 2
- 108090000790 Enzymes Proteins 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 241000223221 Fusarium oxysporum Species 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 244000045947 parasite Species 0.000 claims 1
- 235000013618 yogurt Nutrition 0.000 claims 1
- 210000004215 spore Anatomy 0.000 description 9
- 229920001817 Agar Polymers 0.000 description 7
- 239000008272 agar Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- -1 PF 1022A compound Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004885 tandem mass spectrometry Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 2
- 241000223218 Fusarium Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229930000044 secondary metabolite Natural products 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- VOXXWSYKYCBWHO-QMMMGPOBSA-N (S)-3-phenyllactic acid Chemical compound OC(=O)[C@@H](O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-QMMMGPOBSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 235000002754 Acer pseudoplatanus Nutrition 0.000 description 1
- 241000589158 Agrobacterium Species 0.000 description 1
- 241001116389 Aloe Species 0.000 description 1
- 241000235349 Ascomycota Species 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 240000001548 Camellia japonica Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000221955 Chaetomium Species 0.000 description 1
- 241001149957 Cladosporium oxysporum Species 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- 241000143442 Daldinia Species 0.000 description 1
- 241000253162 Dysderocrates silvestris Species 0.000 description 1
- 241000143682 Hypoxylon Species 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 244000302661 Phyllostachys pubescens Species 0.000 description 1
- 235000003570 Phyllostachys pubescens Nutrition 0.000 description 1
- 241000209466 Platanus Species 0.000 description 1
- 244000268528 Platanus occidentalis Species 0.000 description 1
- 235000006485 Platanus occidentalis Nutrition 0.000 description 1
- 241001493421 Robinia <trematode> Species 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- 240000007660 Sechium edule Species 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 241001523965 Xylaria Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 235000011399 aloe vera Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940022769 d- lactic acid Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- AIUDWMLXCFRVDR-UHFFFAOYSA-N dimethyl 2-(3-ethyl-3-methylpentyl)propanedioate Chemical compound CCC(C)(CC)CCC(C(=O)OC)C(=O)OC AIUDWMLXCFRVDR-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000004383 glucosinolate group Chemical group 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000013048 microbiological method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000003046 sporozoite Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
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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
- C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
-
- 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
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
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- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
201034681 六、發明說明： 【發明所屬技術領域】 本發明係關於—錄制&入> 個環原子的光學活性P : 3魏及苯基乳酸之具有24 之方法，其係藉由 或以這些真菌菌株所分離：音：厌角菌科之真菌菌株’ 之m〇22M顯著的^ 物而得。具有通式⑴ 醫學領域。 的適於抑制内寄生蟲，尤其在醫學及獸
本發明係關於一種製備含乳酸及苯基乳酸之具有24 個環原子的環狀縮紛酸肽類之新方法，上述具有24個環 原子的環狀縮紛酸肽類（八縮盼酸肽類 (octadepsipeptides))及其殺内寄生蟲劑之應用已經是先前 專利申請案（US005571793A)的主題，有一系列的化學 201034681 及微生物學方法以製備含D-2-經基異戍酸之具有24個環原 子的環狀縮紛酸肽類（例如：合成法，參照Ohyama M. et al” Biosci.Biotechnol. Biochem. 58 (1994) pp.1193-1194； Scherkenbeck J.Et al. Tetrahedron 51 (1995) pp. 8459-8470;
Kobayashi M. et al. Annu. Rep. Sankyo Res. Lab. 46 (1994) pp. 67-75; Lee B. et al. Bioorg. Med. Chem. Lett. 12 (2002) pp. 353-356; Dutton FE et al. J.Antibiot. 47 (1994) pp. 1322-1327)。 曰本專利（Sasaki T et al. J. Antibiot. 45 (1992) pp. 692-697; Yanai K et al. Nature Biotechnology 22 (2004) pp. 848-855)說明由真菌菌株幫助含D-乳酸及D-苯基乳酸的 環狀八縮紛酸肽PF1022A之發酵，該真菌菌株已被稱為 “PF1022A菌株”。PF1022A菌株分離自收集於日本茨城 縣（Ibaraki Prefektur)之山茶花植物 葉，該菌株以寄存編號FERMBP-2671寄存於日本國立生 物科學與人類科技研究所工業科學與科技署（National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology)，及以寄存編號 No. IF03 3 096 寄存於大阪發酵學會（institute for Fermentation, Osaka)。由 Meiji Saika Kaisha 有限公司說明之 PF1022A 生產真菌菌株屬於炭角菌科，其最近親緣為白羽紋病菌 (Rosellinia necatrix) IFO 32537 ( Miyadoh S. et al.
Nippon Kingakukai Kaiho 41 (2000), pp. 183-188)及炭角 菌IFO9780 ( Sasaki T et al. J. 5 201034681
Antibiot. 45 (1992)，pp 692-697)，此兩菌株不會產生任何 PF1022A化合物。 【發明内容】 本發明係關於新真菌菌株之發現，該類真菌菌株分 離自生長於落葉及針葉樹之枯木的座間殼菌種之子實= 及其他炭角菌科，以用於製造PF1022A。 由生長於落葉及針葉樹之枯木的座間殼菌種之子實體及 其他炭角菌科的真菌菌株以做為PF1022A潛在活性物質f 形成者之分離說明： 普遍存在的座間殼菌屬歸類於炭角菌科，該科歸於 廣泛的炭角菌目（子囊菌門），此目之典型特徵為具有輪 廓分明小孔之球形子實體（子囊殼(perithecia))，含有抱子 之子囊在此發育。 除座間殼菌屬外’其他褐瘤菌屬（Daldinia)、黑瘤孽 屬（Hypoxylon)、孢子菌屬（proronia)、茶樹黑瘤病菌屬 (Ustulina)及木材菌屬（Xylaria)均歸類於此科。上述每—屬 有一系列可能產生環狀縮酚酸肽類之不同的種。 炭角菌科具有非常堅硬易脆的子囊殼，每一殼八個 棕色至黑色之孢子的子囊位於子囊殼中。座間殼菌屬包括 一系列腐生或内寄生，並且證實為病原體的種，病原種寄 生於落葉與針葉樹之活木材及根系中，該屬之典型腐生種 主要生長於已分解的朽木。在自然環境中，特有的種對溫 度、濕度及光線有相當高的需求，其生長同時與季節（特 6 201034681 別為冬末春初）和高度不受干擾的群落小區有關。可在受 少許影響（若有的話）的森林發現座間殼菌。 、由枯死之落葉林樣本（例如：懸鈴木、刺槐）分離 感興趣之座間殼8真菌ϋ株；然而，由於不同分解程度， 個別枯死木材樣本的樹木麵之屬性無法永遠精核。 由枯木材移出的成熟、完整、分離（如有可能）之 =囊殼得到祕培養物。以濃度G祕贿液表面消 毒並反覆以無菌水沖洗，小心以顯微鏡玻片壓碎子囊殼， 釋出之子囊及孢子移入含無菌水的試管中。 以顯微鏡觀察可能估計孢子的密度與成熟程度；至 於咼孢子岔度，十倍數稀釋孢子懸浮液，每一稀釋步驟取 100微升平板塗佈至麥芽萃取物瓊脂培養基（mea)，該 培養基平板存放於18至2〇。(：，於顯微鏡下每日記錄，並 且將發芽孢子移至新鮮馬鈴薯葡萄糖壤脂培養基 (PDA)，於該培養基形成之菌絲體呈白色淺細長構造， 不形成氣生菌絲體。 培養物充分生長之後，遵照標準方法以甲醇萃取菌 絲體，以液相層析-光電二極體陣列-電離-四極飛行式 質讀儀（LC-PDA-ESI-Q-TOF_MS )及串聯式質譜儀 (MS/MS)鑑定菌絲體萃取物之成分及定量PF1022A之 含量’發現不同座間殼菌品系’這些品系被證實與形成 PF1022A 有關。 依據形態特徵，六種PF1022A產生者被認定為下列種類： Ja9 洛葉林之附抱座間殼菌（)(無法進 7 201034681 一步詳細測定）
Jal5=來自於懸龄木之附抱座間殼菌（及叫w//a) Jal6=來自於落葉林之座間殼菌屬（如北)(無法 進一步詳細測定）
Jal9 =來自於刺槐或懸鈴木之附孢座間殼菌或克堤昆座 間殼菌（/?. corhcww )
Ja21 -洛葉林之克堤昆座間殼菌（無法進一步詳細測定） Ja26=落葉林之座間殼菌屬（無法進一步詳細測定） 進行培養貫驗’與無抱菌T38-18 (il^yce/ί'α T38-18) 野生型、艾司康狄塔座間殼菌（及⑽e//z_m'a ahc⑽而β)菌株CBS 448.89及CBS 450.89比較，新分離 之真菌菌株於MEA、mPDA、CMA培養基及種子培養基 (seed agar)上顯示生長較快。 生長於21至22°C，10至12天之附孢座間殼菌Ja-9、 附孢座間殼菌Ja-15與座間殼菌屬ja_i6培養物可生長至 培養皿的邊緣（9公分），而對照的培養物無孢菌丁38_18 “野生型”、艾司康狄塔座間殼菌CBS 448.89及艾司康狄塔 座間殼菌CBS 450.89卻顯著的以較短的直徑為特色，這 表示新的座間殼菌菌株特色為生長較快；菌株附孢座間殼 菌或克堤昆座間殼菌Ja-19、克堤昆座間殼菌ja_21及座間 殼菌屬Ja-26生長同樣快。 細長之il絲體生長於MEA及mPDA培養基，而緻 密而纏結（在某些情況下）之菌絲體形成於高營養培養基 201034681 CMA及種子培養基。於M1培養基上分離株仏_19與以_加 形成外觀部分似羽毛的菌絲體。 使用培養基之成分： CMA .玉米粉50公克/公升，瓊脂15公克/公升 M1 ·麥芽萃取物10公克/公升，酵母菌萃取物4公克/公 升，葡萄糖4公克/公升，瓊脂15公克/公升
Seedagar .藥培養基（pharmamedia) 20公克/公升，大豆 蛋白脒2克/公升，麥芽糖40克/公升及七結晶 水硫酸鎂2克/公升，氯化鈉2克/公升，碳^ 鈣3克/公升，瓊脂15公克/公升 MEA:麥芽萃取物17公克/公升，瓊脂15公克/公升 mPDA .葡萄糖5公克/公升，馬鈴薯澱粉2〇公克/公升， 酵母菌萃取物1.5公克/公升，瓊脂15公克/公升 由於目前之培養物是直接由自然生態系移至人工環 境之分離株，可能產生形成不同菌絲體形狀與關於形成不 同程度的活性物質之栽培品種。 【實施方式】 9 201034681 以LC-PDA-ESI-Q_TOF-MS及MS/MS鑑定新分離菌株之 菌絲體萃取物的成分（特別是PF1022A)與無孢菌T38-18 · 野生型比較之說明： 為了鑑定組成成分（特別是PF1022A化合物），使 用一種摘測器、光電二極體陣列（photodiode array ; PDA ) 及質譜儀（MS)兩偵測儀之高效液相層析法（HPLC)研 究無孢菌T38-18野生型與新分離株ja-9、Ja-15、Ja-16、 Ja-19、ja-21與Ja-26之曱醇菌絲體萃取物。 藉由光電二極體陣列及質譜儀偵測之高效液相層析ί》 法’該研究可比較無孢菌Τ38-18野生型與新分離株Ja-21 的甲醇菌絲體萃取物之成分，顯示上述品種的產生成分之 明顯差異如下： 無孢菌野生塑產生一系列PF1022化合物：PF1022-A (C52H76N4012)、PF1022-B ( C64H84N4012)、PF1022-C (C58H8〇N4〇i2 ) ' PF1022-D ( C46H72N4012 ) > PF1022-E (C52H76N4〇13)及 PF1022-F (C49H68N4012);除了新分離 株之外（例如Ja-21) ’這些化合物以PF1022-A (於光電U -~極體陣列及質譜儀 <貞測之層析圖的滞留時間（retention time ; Rt) : 25.1 至 25.6 分鐘）與 PH022-D (滯留時間： 19·5至20分鐘）為主要成分。 PF1022-A (以液相層析光電二極體陣列質譜儀 (LC-PDA-MS )加上紫外光/可見光(UV/V)與質譜儀數據 及滯留時間定性，與無孢菌之PF1022A相較，具有在高效 液相層析圖的相同滯留時間之同一分子量）與其他不屬於 201034681 主要成分PF1022之化合物（滯留時間：12 么至24分鐘) 也產生PF1022-B及-C為次級化合物，但實際上沒有 PF1022-D ;也未發現化合物PF1022-E及-F。、^ 比較無抱菌野生型與新分離株以_15及；^9之總離 子層析質諸圖（TIC-MS)也發現相同結果；以液相芦析_ 光電二極體陣列-電離-四極飛行式質譜儀及串聯^質譜 儀對PF1022A化合物進行進一步鑑識研究。 ”貝°曰 也比較無孢菌野生型與新分離株ja_15及Ja_l9之菌 絲體萃取物的PF1022A化合物於液相層析串聯式質 (LC-MS/MS)層析圖的選取尖峰’這些尖峰有相同^留 時間，於串聯式質譜儀偵測之無孢菌野生型與新分離株 Ja-15及Ja-19菌絲體萃取物之PF1022A化合物的質量 949.6之質子加合物串聯式質譜儀片段彼此相同。 上述液相層析-光電二極體陣列-電離—四極飛行 式質譜儀及串聯式質譜儀之研究結果證實新分離株如
Ja-15、Ja-19 及 Ja-21 也與 Ja-9、Ja-16 及 Ja_26 並非無 孢菌野生型，但也產生PF1022A化合物。 與無孢菌野生型相較，由於新的座間殼菌與木材菌 品種不產生次級化合物PF1022-D、-E及-F，萃取及分離 PFl〇22A方法極其簡單。 【圖式簡單說明】 【主要元件符號說明】 % 11
Claims (1)
- 201034681 七、申請專利範圍： 1. 一種製備具下式之PF1022A之方法，其係為具有24個環原ί 子的環狀縮酚酸肽類，該方法係藉由座間殼菌種及炭角菌' 科的其他屬之真菌菌株，或藉由這些真菌菌株所分離之酵-素製備物之輔助而得2.根據申請專利範圍第1項之製備PF1022A之方法，其係藉 由座間殼菌及其他炭角菌科之真菌菌株，特別是附孢座間 殼菌（)或克堤昆座間殼菌（ coh/cwm)之輔助而得。 12 201034681 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 無五、本案若有化學式時，請揭示最能顯示發明特徵的化 學式： 201034681 發明鼻利說明書(本說明書格式 ，請勿任意更動’※記號部分請勿填寫） 分類： I ※申請案號：/4$( ※申請曰：u Jt \> 一、發明名稱：（中文/英文） 以座間殼菌及其他炭角菌科之真菌菌株製備含乳酸及苯基 乳酸之具有24個環原子的光學活性環狀縮盼酸肽類 (depsipeptides)之方法 Process for the preparation of lactic- and phenyllactic-acid-containing, optically active, cyclic depsipeptides with 24 ring atoms with the aid of fungal strains of Rosellinia species and further Xylariaceae 二、中文發明摘要： 學及獸醫學領域。 本發明係關於一種製備含乳酸及苯基乳酸之具有24 個％原子的光學活性環狀縮酚酸肽類之方法，其藉由座間 殼菌及其他炭錢科之真難株，或藉由這些真g菌株所 分離之酵素製備物而得，賴真Kg株不但可由生長於落 葉與針葉樹之枯死及活木材的座間㈣種及炭角菌之子實 體分離，射直接由落葉與針葉狀木材與根分離。具有 通式(I)之PFIGUA係顯著的適於抑制内寄生蟲，尤其在醫 201034681 發明鼻利說明書(本說明書格式 ，請勿任意更動’※記號部分請勿填寫） 分類： I ※申請案號：/4$( ※申請曰：u Jt \> 一、發明名稱：（中文/英文） 以座間殼菌及其他炭角菌科之真菌菌株製備含乳酸及苯基 乳酸之具有24個環原子的光學活性環狀縮盼酸肽類 (depsipeptides)之方法 Process for the preparation of lactic- and phenyllactic-acid-containing, optically active, cyclic depsipeptides with 24 ring atoms with the aid of fungal strains of Rosellinia species and further Xylariaceae 二、中文發明摘要： 學及獸醫學領域。 本發明係關於一種製備含乳酸及苯基乳酸之具有24 個％原子的光學活性環狀縮酚酸肽類之方法，其藉由座間 殼菌及其他炭錢科之真難株，或藉由這些真g菌株所 分離之酵素製備物而得，賴真Kg株不但可由生長於落 葉與針葉樹之枯死及活木材的座間㈣種及炭角菌之子實 體分離，射直接由落葉與針葉狀木材與根分離。具有 通式(I)之PFIGUA係顯著的適於抑制内寄生蟲，尤其在醫 201034681 三、英文發明摘要： The present invention relates to a process for the preparation of lactic- and phenyllactic-acid-containing, optically active, cyclic depsipeptides with the 24 ring atoms by means of fungal strains of the genus Rosellinia and further Xylariaceae isolated not only from fruiting bodies of Rosellinia spp. and Xylariaceae growing on dead timber and live timber of deciduous and coniferous trees, but also directly from timber and roots of deciduous and coniferous trees, or by means of enzymatic preparations isolated from these fungal strains. PF1022A, of the general formula (I), is outstanding suitable for controlling endoparasites, in particular in the field of medicine and veterinary medicine. 2
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| AU2016380868B2 (en) | 2015-12-28 | 2019-11-28 | Boehringer Ingelheim Animal Health USA Inc. | Anthelmintic depsipeptide compounds |
| CN108570016B (zh) * | 2017-03-10 | 2021-11-26 | 上海医药工业研究院 | 一种pf1022a分离纯化的方法 |
| WO2018166899A1 (en) | 2017-03-14 | 2018-09-20 | Acidophil Ltd | Methods for production of pf1022a derivatives |
| CN109880746B (zh) * | 2017-12-06 | 2023-10-20 | 海正药业(杭州)有限公司 | 一种座坚壳属真菌菌株及其应用 |
| WO2020018888A1 (en) | 2018-07-20 | 2020-01-23 | The Board Of Regents Of The University Of Oklahoma | Antimicrobial peptides and methods of use |
| CN110964646B (zh) * | 2019-11-15 | 2021-07-27 | 成都大学 | 一种座坚壳菌、应用、发酵培养基及pf1022a的制备方法 |
| CN115247132B (zh) * | 2021-04-26 | 2024-04-16 | 中国科学院微生物研究所 | 一种组合型人工生物结皮治理荒漠的方法 |
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| DOP2011000182A (es) | 2011-07-15 |
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| SV2011003943A (es) | 2011-11-08 |
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