JPH0341089A - Physiologically active substance 3127 - Google Patents
Physiologically active substance 3127Info
- Publication number
- JPH0341089A JPH0341089A JP1176933A JP17693389A JPH0341089A JP H0341089 A JPH0341089 A JP H0341089A JP 1176933 A JP1176933 A JP 1176933A JP 17693389 A JP17693389 A JP 17693389A JP H0341089 A JPH0341089 A JP H0341089A
- Authority
- JP
- Japan
- Prior art keywords
- spectrum
- reaction
- active substance
- physiologically active
- methanol
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 239000013543 active substance Substances 0.000 title claims description 15
- 239000000126 substance Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 9
- 238000001228 spectrum Methods 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 239000000843 powder Substances 0.000 abstract description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 4
- 102000004225 Cathepsin B Human genes 0.000 abstract description 4
- 108090000712 Cathepsin B Proteins 0.000 abstract description 4
- 241000228138 Emericella Species 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000000921 elemental analysis Methods 0.000 abstract description 3
- 238000002844 melting Methods 0.000 abstract description 2
- 230000008018 melting Effects 0.000 abstract description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003208 petroleum Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 108090000145 Bacillolysin Proteins 0.000 abstract 1
- 102000035092 Neutral proteases Human genes 0.000 abstract 1
- 108091005507 Neutral proteases Proteins 0.000 abstract 1
- 150000001450 anions Chemical class 0.000 abstract 1
- 150000001768 cations Chemical class 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000001419 dependent effect Effects 0.000 abstract 1
- 238000004949 mass spectrometry Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- 229920001817 Agar Polymers 0.000 description 7
- 239000008272 agar Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 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 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 102000007590 Calpain Human genes 0.000 description 3
- 108010032088 Calpain Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 2
- 241000235349 Ascomycota Species 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000006938 muscular dystrophy Diseases 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000011218 seed culture Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000007211 ypss medium Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 1
- HORQAOAYAYGIBM-UHFFFAOYSA-N 2,4-dinitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O HORQAOAYAYGIBM-UHFFFAOYSA-N 0.000 description 1
- AUUIARVPJHGTSA-UHFFFAOYSA-N 3-(aminomethyl)chromen-2-one Chemical compound C1=CC=C2OC(=O)C(CN)=CC2=C1 AUUIARVPJHGTSA-UHFFFAOYSA-N 0.000 description 1
- CTIHYOZNWNAKHD-UHFFFAOYSA-N 4-methoxybenzaldehyde;sulfuric acid Chemical compound OS(O)(=O)=O.COC1=CC=C(C=O)C=C1 CTIHYOZNWNAKHD-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 101100539386 Caenorhabditis elegans uda-1 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- ZZGDDBWFXDMARY-SVBPBHIXSA-N benzyl n-[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC1=CC=2OC(=O)C=C(C=2C=C1)C)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 ZZGDDBWFXDMARY-SVBPBHIXSA-N 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000018842 conidium formation Effects 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940096118 ella Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野]
本発明は、
蛋白質分解酵素阻害作用を有する、
更に詳しくは、
カルシウム依存性中性プロテア−
ゼ
カテプシンB阻害作用を有する新規なペプチド化合物に
関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel peptide compound having a protease inhibitory effect, and more particularly, a novel peptide compound having a calcium-dependent neutral protease cathepsin B inhibitory effect.
[従来の技術]
カルシウム依存性中性プロテアーゼ、カテプシンBに対
して阻害作用を有するペプチドとしては、ロイペプチン
や特公昭59−34711号公報、特公昭60−371
05号公報に示されているE−64が知られている。[Prior Art] Examples of peptides having an inhibitory effect on calcium-dependent neutral protease and cathepsin B include leupeptin, Japanese Patent Publication No. 59-34711, and Japanese Patent Publication No. 60-371.
E-64 shown in Publication No. 05 is known.
[発明が解決しようとする課題]
カルシウム依存性中性プロテアーゼ(CAMPと略称す
る)は筋ジストロフィーにおける筋蛋白質分解酵素とし
て、また力テプシンBは、骨ノ異常代謝、ライソゾーム
病、f5萎縮症、癌の転移に関する蛋白分解酵素として
知られており、その阻害剤は、現代の難病の治療薬とし
て有望視されている。そのため、CAMP、カテブシン
Bに対して阻害活性を有する薬剤の開発が強く望まれて
いる。[Problems to be solved by the invention] Calcium-dependent neutral protease (abbreviated as CAMP) is a muscle proteolytic enzyme in muscular dystrophy. It is known as a proteolytic enzyme involved in metastasis, and its inhibitors are considered promising as therapeutic agents for modern incurable diseases. Therefore, the development of a drug having inhibitory activity against CAMP and cathebusin B is strongly desired.
[課題を解決するための手段]
本発明者らは、生理活性を有する新規物質を土壊分離菌
の中から得るべく探索研究を重ねた結果、本発明者らの
見出した特定の微生物が、蛋白質分解酵素阻害作用を有
する新規な生理活性物質を生産することを見出し本発明
を完成するに至った。[Means for Solving the Problems] As a result of repeated exploratory research in order to obtain a new biologically active substance from soil destruction bacteria, the present inventors discovered that a specific microorganism The present invention was completed by discovering the production of a new physiologically active substance that has a proteolytic enzyme inhibitory effect.
本発明の式(I) NH。Formula (I) of the present invention N.H.
で表わされる生理活性物質3127を生産する菌株は、
本発明者らが、埼玉県大宮市で採取した土壌より新たに
分離した菌株であり、微生物の名称’ Emarice
lla n1dulans F−3127Jおよび微生
物寄託番号「微工研菌寄第10797号(FERM
P−10797」として、工業技術院微生物工業技術研
究所に寄託されているものである。The strain that produces the physiologically active substance 3127 represented by
This strain was newly isolated by the present inventors from soil collected in Omiya City, Saitama Prefecture, and the name of the microorganism is 'Emarice.
lla n1dulans F-3127J and microorganism deposit number “FERM
P-10797, which has been deposited with the Institute of Microbial Technology, Agency of Industrial Science and Technology.
この菌株の菌学的性状を以下に示す。The mycological properties of this strain are shown below.
■ 形態
本菌株は麦芽汁寒天培地、バレイショ・ブドウ糖寒天培
地、YpSS寒天培地などで良好に生育し、分生子の形
成は上記寒天培地の他にもツアッペク寒天培地やオート
ミル寒天培地などでも良好である。バレイショ・ブドウ
糖寒天培地に生育したコロニーを顕微鏡下で観察すると
、菌糸は隔壁を有し、高度に分枝しており、分生子柄は
滑面でやや茶褐色を呈し、長さは35〜120μと変化
に富み、その径は基部でa、o−4,oμ、先端付近(
頂嚢下部)では4.0〜5.0P、である、頂嚢は、半
球形フラスコ状で直径9.0〜15JJ11.通常、頂
嚢1/2ぐらいに、ブイアライドが放射状に複列に形成
されている。大きさは基底ブイアライド(メトリ)が5
〜7X2〜3.5μ、先端ブイアライドが5〜6×2〜
3Pである。 分生子はブイアライドの先端から連鎖状
に形成されるフィアロ型分生子であり、長さ100μ以
下の短円柱形の分生子頭を形成する。電子顕微鏡下で観
察すると分生子は球形で隔壁は無く、暗灰緑色から黄緑
色を呈し、大きさは直径2.8〜3.8μであり、その
表面はしわ状で粗面を呈している。■ Morphology This strain grows well on wort agar, potato/dextrose agar, YpSS agar, etc., and conidia formation is also good on Zappek agar, oatmil agar, etc. in addition to the above agar media. . When colonies grown on potato glucose agar were observed under a microscope, the hyphae had septa and were highly branched, and the conidiophores were smooth and slightly brown in color, with a length of 35 to 120 μm. It is highly variable, with diameters ranging from a, o-4, oμ at the base to around the tip (
The apical capsule has a hemispherical flask shape and a diameter of 9.0 to 15JJ11. Usually, buialides are formed in double rows radially in about 1/2 of the apical capsule. The size is 5 for the basal buoyancy (metri).
~7x2~3.5μ, tip buoylide 5~6x2~
It is 3P. Conidia are phialoid conidia that are formed in a chain from the tip of the buialide, forming short cylindrical conidial heads with a length of 100 μm or less. When observed under an electron microscope, the conidia are spherical, have no septa, exhibit a dark gray-green to yellow-green color, and have a diameter of 2.8 to 3.8 μ, with a wrinkled and rough surface. .
子嚢果の形成は培養10日前後から観察され、開口部の
ない、いわゆる閉子麦殻を形成する。Formation of ascocarps is observed from around 10 days after culturing, and they form so-called cleistocarps without openings.
閉鎖子嚢果は赤紫色、球形から亜球形で大きさは直径1
70〜250Pであり、その表面を渋茶褐色ドーナツ状
直径12〜120μmのホールセル(Hall Ca1
l )が覆っている。子嚢は球形から亜球形で大きさは
直径8.0〜9.27J11.内部に赤紫色、レンズ形
の子嚢胞子を8個含んでいる。子嚢胞子を電子顕微鏡下
で観察すると、直径は3゜5〜4.BP、レンズ面は滑
面を呈している。赤道面に2枚の波状に屈曲した隆起を
形成しており、周縁は丸く、やや反り返り、規則的なひ
だが放射状に並んでいる。The atretic asci are reddish-purple, spherical to subglobose, and 1 in diameter.
70 to 250P, and its surface is covered with a dark brown donut-shaped whole cell (Hall Ca1) with a diameter of 12 to 120 μm.
l) is covered. The asci are spherical to subglobular and the size is 8.0 to 9.27 J11. The inside contains eight reddish-purple, lens-shaped ascospores. When ascospores are observed under an electron microscope, the diameter is 3.5-4. BP, the lens surface exhibits a smooth surface. It forms two wavy ridges on the equatorial plane, with rounded edges, slightly curved, and regular folds arranged in a radial pattern.
■ 培地上での諸性状
各種培地上で30’C,14日間培養した場合の肉眼的
観察結果を次の表1に示した。(2) Properties on media The following Table 1 shows the results of macroscopic observation when cultured on various media at 30'C for 14 days.
表1
■ 生理的、生態的性質
1)最適生育条件
本菌株の最適生育条件は、YpSs培地においてpH7
〜8、温度34〜40”Cである。Table 1 ■ Physiological and ecological properties 1) Optimal growth conditions The optimal growth conditions for this strain are YpSs medium at pH 7.
~8, temperature 34-40''C.
2)生育範囲
本菌株の生育範囲はYpSs培地においてpH3〜9、
温度10〜49℃である。2) Growth range The growth range of this strain is pH 3 to 9 in YpSs medium.
The temperature is 10-49°C.
3)好気性、嫌気性の区別;好気性
以上の形態的特徴および培養上の性状から、本菌株が、
子嚢菌亜門、不整子嚢菌網に属することが明らかであり
、子嚢果や子fA胞子の特徴および不完全世代の特徴を
基に、宇田用俊−1椿啓介偏「菌類図鑑、(1978)
およびレイパー(Raper)、フェンネル(Fenn
ell)プ(著の「ザ・ジーナス・アスペルギルス(T
he Genus Aspergillus )(19
65)Jに報告されている多くの既知菌株と比較検討し
た。その結果、本菌株はEmericella n1d
ulans (Eidam)Vuillに最も近い性状
を示すことが明らかとなり、本菌株を’ Emeric
ella n1du1ans−F−3127Jと命名し
た。3) Distinction between aerobic and anaerobic; from the morphological characteristics and culture characteristics that are more than aerobic, this strain is
It is clear that it belongs to the subphylum Ascomycota and the asymmetric ascomycete network, and based on the characteristics of ascocarps and ascospores and the characteristics of incomplete generation, Yoshitoshi Uda-1 Keisuke Tsubaki, "Illustrated Encyclopedia of Fungi," (1978) )
and Raper, Fennel
``The Genus Aspergillus (T.
he Genus Aspergillus ) (19
65) A comparative study was conducted with many known bacterial strains reported in J. As a result, this strain was Emericella n1d
ulans (Eidam) Vuill, and this strain was designated as 'Emeric.
It was named ella n1du1ans-F-3127J.
次に、生理活性物質3127の生産であるが、これは大
略一般発酵生産物を生産する場合に準じて行なわれる。Next, the production of the physiologically active substance 3127 is carried out roughly in the same manner as in the production of general fermentation products.
すなわち、各種の栄養物質を含む培地でEmerice
lla n1dulans−F −3127株を好気的
条件下で培養する。That is, Emerice is grown in a medium containing various nutritional substances.
llan1dulans-F-3127 strain is cultured under aerobic conditions.
培地は主として液体培地を用い、炭素源としてはグルコ
ース、廃糖蜜、スターチなどを単独または混合して用い
ることができる。窒素源としてはポリペプトン、大豆粉
、酵母エキスなどを単独かまたは混合して用いることが
できる。その他、菌株の生育を助は生理活性物質312
7の生産を促進する有機物および無機塩を必要により添
加することができる。消泡剤としては、アデカノール、
シリコンなどを用いるこ゛とができる。A liquid medium is mainly used as the medium, and glucose, molasses, starch, etc. can be used alone or in combination as a carbon source. As the nitrogen source, polypeptone, soybean flour, yeast extract, etc. can be used alone or in combination. In addition, 312 physiologically active substances help the growth of bacterial strains.
Organic substances and inorganic salts that promote the production of No. 7 can be added as necessary. As an antifoaming agent, Adekanol,
This can be done using silicon or the like.
培養方法は振とう培養、通気攪拌培養などの好気培養が
適しており、pH3〜7.25〜37℃で、2〜5日間
、望ましくは、pH6〜7.28〜30℃で3〜4日間
培養する。For the culture method, aerobic culture such as shaking culture or aerated agitation culture is suitable, and the pH is 3-7.25-37°C for 2-5 days, preferably pH 6-7.28-30°C for 3-4 days. Incubate for days.
この培養液中に生産された生理活性物質3127を単離
するには、発酵生産物を採取する一般的な方法に準じて
行なえば良い、すなわち培養終了後、遠心分離または濾
過により分離した培養濾液をダイヤイオンHP−20(
商品名;三菱化成製)などに吸着させ、低級アルコール
等にて溶出する。溶出された生理活性物質3127の両
分を濃縮後、酢酸エチルエステル、クロロホルムなどの
非水溶媒に転溶し、濃縮してシロップ状とする。このシ
ロップを再度、酢酸エチルエステル、クロロホルムなど
の有機溶媒に溶解し、シリカゲルを用いたカラムクロマ
トグラフ、セファデックスLH−20(商品名;ファル
マシア社製)を用いたゲル濾過およびクロマトレックス
(商品名;富士−デビソン化学社製)を用いたカラムク
ロマトグラフに付し、活性成分を集めることにより、−
形式(I)で表わされるトリペプチド誘導体を精製単離
することができる。The physiologically active substance 3127 produced in this culture solution can be isolated by following the general method of collecting fermentation products, i.e., the culture filtrate is separated by centrifugation or filtration after the completion of the culture. The Diamond Ion HP-20 (
Adsorb it with a product such as (trade name: manufactured by Mitsubishi Kasei) and elute with a lower alcohol, etc. Both parts of the eluted physiologically active substance 3127 are concentrated, then transferred to a nonaqueous solvent such as ethyl acetate or chloroform, and concentrated to form a syrup. This syrup was dissolved again in an organic solvent such as ethyl acetate or chloroform, and subjected to column chromatography using silica gel, gel filtration using Sephadex LH-20 (trade name; manufactured by Pharmacia), and chromatrex (trade name). ; manufactured by Fuji Davison Chemical Co., Ltd.) to collect the active ingredients, -
Tripeptide derivatives of format (I) can be purified and isolated.
以上の精製法によって得られた生理活性物質3127は
、その元素分析値1分子量、紫外線スベクトル、赤外線
スペクトル、’H−NMRスペクトル、”C−NMRス
ペクトルの解析によりその構造式が次の如く決定された
。The structural formula of the physiologically active substance 3127 obtained by the above purification method was determined as follows by analysis of its elemental analysis value, molecular weight, ultraviolet spectral, infrared spectrum, 'H-NMR spectrum, and 'C-NMR spectrum. It was done.
(構造式)
%式%)
:
:
)
)
)
(4)元素分析値;C□H4t N s Otとして計
算値(%);C57゜65.H8,75,N 12.9
3゜020.64゜
実測値(%) ; C57,94,H8,63,N 1
2.88゜020.55
(5〉分子量=541
(6)[α] ニー31.0゜
(c−0,1,メタノール溶液)
(7)UV吸収スペクトル:
エタノール溶液で測定した結果、
末端吸収を
示す。(Structural formula) % formula %) : : ) ) ) (4) Elemental analysis value; Calculated value (%) as C□H4tNsOt; C57°65. H8,75,N 12.9
3゜020.64゜Actual value (%); C57,94, H8,63, N 1
2.88゜020.55 (5〉Molecular weight = 541 (6) [α] Knee 31.0゜ (c-0,1, methanol solution) (7) UV absorption spectrum: As a result of measurement with ethanol solution, terminal absorption shows.
(8)IR吸収スペクトル: KBr錠中で測定したスペクトルを第1図に示す。(8) IR absorption spectrum: The spectrum measured in the KBr tablet is shown in FIG.
(9)’H−NMRスペクトル:
重ジメチルスルフオキシド(d 、−DMSO)中、4
00MHzで測定したスペクトルを第2図に示す。(9)'H-NMR spectrum: 4 in deuterated dimethyl sulfoxide (d, -DMSO)
The spectrum measured at 00 MHz is shown in FIG.
〈10)ロC−NMRスペクトル:
重ジメチルスルフオキシド中、100MHzで測定した
スペクトルを第3図に示す。<10) RoC-NMR spectrum: The spectrum measured at 100 MHz in deuterated dimethyl sulfoxide is shown in FIG.
〈11〉溶解性: メタノール、酢酸、DMSOに易溶。<11> Solubility: Easily soluble in methanol, acetic acid, and DMSO.
酢酸エチルエステル、クロロホルム、アセトンに難溶。Slightly soluble in acetic acid ethyl ester, chloroform, and acetone.
n−ヘキサン、石油エーテル、エチルエーテル、水に不
溶。Insoluble in n-hexane, petroleum ether, ethyl ether, water.
(12)呈色反応:
陽性:沃素、ライドン−スミス、2,4−ジニトロフェ
ニルヒドラジン(2,4−DNP)、トリフェニルテト
ラゾリウムクロライド(TTC)
陰性:硫酸、アニスアルデヒド−硫酸、バニリン−硫酸
、ニンヒドリン
(13〉塩基性、酸性、中性の区別:中性[発明の効果
]
本発明の生理活性物質3127は、CAMP。(12) Color reaction: Positive: iodine, Lydon-Smith, 2,4-dinitrophenylhydrazine (2,4-DNP), triphenyltetrazolium chloride (TTC) Negative: sulfuric acid, anisaldehyde-sulfuric acid, vanillin-sulfuric acid, Ninhydrin (13> Basic, acidic, neutral: neutral [Effects of the invention] The physiologically active substance 3127 of the present invention is CAMP.
カテブシンBに対して阻害活性を有するので筋ジストロ
フィーなどの治療薬として有用である。Since it has inhibitory activity against cathebusin B, it is useful as a therapeutic agent for muscular dystrophy and the like.
[実施例]
以下、実施例および試験例を挙げて本発明を具体的に説
明する。[Example] Hereinafter, the present invention will be specifically explained with reference to Examples and Test Examples.
実施例1
(1) 100mQ当り、グルコ〜ス4g、ポリペプ
トン1gを含む無菌液体培地にEmericella
n1clulans−F−3127株を接種し、30°
C196時間振とう培養した。次、に、内容量50p、
のジャーファーメンタ−を用いて、種培養と同じ組成の
無菌培地30p、、タンク(内容量2o0i)には12
01入れ、前記種培養液を各々0.31.1゜22を接
種し、30″C188時間通気攪拌、培養した。Example 1 (1) Emericella was added to a sterile liquid medium containing 4 g of glucose and 1 g of polypeptone per 100 mQ.
Inoculated with n1clulans-F-3127 strain and incubated at 30°
Cultured with shaking for 196 hours. Next, content 50p,
Using a jar fermenter, add 30p of sterile medium with the same composition as the seed culture, and 12p to a tank (inner capacity 2o0i).
0.01 and inoculated with 0.31.1°22 of each of the above seed culture solutions, and cultured at 30"C with aeration for 188 hours.
(2)培養終了後、ジャーファーメンタ−3基、タンク
1基分の培養液210p、を濾過し、得られた濾液20
02をダイヤイオンHP−20(商品名;三菱化成工業
株式会社製)52に吸着させ、75%メタノール溶液お
よびメタノール151にて溶出し、さらに溶出液を2e
に濃縮した。この濃縮液を等量の酢酸エチルエステルで
2回抽出した。濾液から得られた酢酸エチルエステル層
と菌体から得られた酢酸エチルエステル層を合わせて、
無水硫酸ナトリウムで脱水後、濃縮し褐色のシロップ状
物質38gを得た。(2) After culturing, 210 p of the culture solution for 3 jar fermenters and 1 tank was filtered, and the resulting filtrate 20
02 was adsorbed on Diaion HP-20 (trade name; manufactured by Mitsubishi Chemical Industries, Ltd.) 52, eluted with a 75% methanol solution and methanol 151, and the eluate was further purified with 2e.
Concentrated into This concentrate was extracted twice with equal volumes of acetic acid ethyl ester. Combine the ethyl acetate layer obtained from the filtrate and the ethyl acetate layer obtained from the bacterial cells,
After dehydration with anhydrous sodium sulfate, the mixture was concentrated to obtain 38 g of a brown syrupy substance.
<3〉 シロップ状物質38gをクロロホルム100
m1に溶解し、クロロホルムで調製したシリカゲルを充
填した250mMのカラムに吸着させ、クロロホルム5
00m1で洗浄後、クロロホルム−メタノール(80:
20)の混合溶媒12で溶出した画分を集め、粗粉末4
00+rgを得た。<3> 38g of syrup-like substance to 100g of chloroform
ml and adsorbed onto a 250mM column packed with silica gel prepared with chloroform.
After washing with 00ml, chloroform-methanol (80:
The fractions eluted with the mixed solvent 12 of 20) were collected, and the crude powder 4 was collected.
00+rg was obtained.
(4)前項の粗粉末40(Igを、75%メタノール溶
液10m1!に溶解し、同じ溶媒で調製したクロマトレ
ックス(商品名、富士−デビソン化学社製)に付し、同
じ組成の溶媒で溶出し、得られた活性画分を集め濃縮乾
固し、黄色粉末130■を得た。(4) The coarse powder 40 (Ig) from the previous section was dissolved in 10 ml of 75% methanol solution, applied to Chromatorex (trade name, manufactured by Fuji-Davison Chemical Co., Ltd.) prepared with the same solvent, and eluted with a solvent of the same composition. The obtained active fractions were collected and concentrated to dryness to obtain 130 ml of yellow powder.
(5〉前項で得られた黄色粉末130t+gをメタノー
ル10mQに溶解し、同じ溶媒で調製したり、H−20
(商品名;ファルマシア社製)に付し、同じ組成の溶媒
で溶出し、得られた活性画分を集めた。(5> Dissolve 130t+g of the yellow powder obtained in the previous section in 10mQ of methanol, prepare with the same solvent, or
(trade name; manufactured by Pharmacia) and eluted with a solvent of the same composition, and the obtained active fractions were collected.
この溶液を75%メタノール溶液になるように調製し逆
相高速液体クロマトグラフィー(センシューパック、
0DS−4251−U 、直径10m×長さ250m、
センシュー科学社製)に付し、カラム温度50℃、流速
4Tnll/分、75%メタノールで繰り返し溶出し、
保持時間が7分前後の両分を集めて濃縮乾固し、白色粉
末6,5■を得た。この白色粉末の融点を測定したとこ
ろ177〜179℃であった。This solution was prepared as a 75% methanol solution and subjected to reverse phase high performance liquid chromatography (Senshu Pack,
0DS-4251-U, diameter 10m x length 250m,
(manufactured by Senshu Kagaku Co., Ltd.) and repeatedly eluted with 75% methanol at a column temperature of 50°C and a flow rate of 4 Tnll/min.
Both fractions with a retention time of around 7 minutes were collected and concentrated to dryness to obtain 6.5 lbs. of white powder. The melting point of this white powder was measured to be 177-179°C.
試験例1(CAMPに対する阻害活性)(試験方法)
1007JIの1.2%カゼイン溶液、200μの10
0mMグリセロリン酸ナトリウム−塩酸溶液(pH7,
5)、54の50mM塩化カルシウム溶液および50μ
の250mMの2−メツしカプトエタノールを混和し反
応溶媒とした。この反応溶液に目的濃度になるように調
製した生理活性物質3127を50μ加え、30℃で5
分間インキュベートした後、更に50dCAMP溶液(
豚赤血球μm CAM P 、 200 u/rNl/
rd)を加え、30°Cで20分間反応させた。10%
トリクロロ酢酸500、Qを加えて反応を止め、60分
放置後遠心し、上清のA1.を測定した。Test Example 1 (Inhibitory activity against CAMP) (Test method) 1.2% casein solution of 1007JI, 200μ of 10
0mM sodium glycerophosphate-hydrochloric acid solution (pH 7,
5), 54 50mM calcium chloride solution and 50μ
250mM of 2-metallic acid and captoethanol were mixed therein to serve as a reaction solvent. Add 50μ of physiologically active substance 3127 prepared to the desired concentration to this reaction solution, and
After incubating for a minute, add 50 dCAMP solution (
Porcine red blood cells μm CAM P, 200 u/rNl/
rd) was added and reacted at 30°C for 20 minutes. 10%
The reaction was stopped by adding trichloroacetic acid 500, Q, and after being left for 60 minutes, it was centrifuged, and the supernatant A1. was measured.
(結果)
IC,。値は、0.5μMであった。また、E−64の
IC,。値は、3.0μMであった。(Result) IC,. The value was 0.5 μM. Also, the E-64 IC. The value was 3.0 μM.
試験例2(カテプシンBに対する阻害活性)(試験方法
)
0.25mMの0.4Mリン酸バッフy−(pH6,0
)に8mM−ジチオスレイトールおよび4mM−EDT
Aを含む溶液に10〜1100nのカテブシンBをo、
i%ブリジ(Br1ji) 35を含む0.5mMの溶
液に溶かし、1■/mlの生理活性物13127のジメ
チルスルホキシド溶液を目的濃度となるように加えて3
7℃で5分間インキュベートした。Test Example 2 (Inhibitory activity against Cathepsin B) (Test method) 0.25mM 0.4M phosphate buffer y-(pH 6,0
) with 8mM-dithiothreitol and 4mM-EDT
Add 10 to 1100 n of catebusin B to a solution containing A,
Dissolve in a 0.5mM solution containing i% Br1ji 35, add 1/ml dimethyl sulfoxide solution of physiologically active substance 13127 to the desired concentration, and mix.
Incubate for 5 minutes at 7°C.
次に、Z −Phe−Arg−NMec(基質)を加え
、10分間反応させた後、ITnIlの100mM−モ
ノクロル酢酸ナトリウムを含む0.1M−酢酸バッファ
ー(pH=4.3)を加えて反応を停止させた。Next, Z -Phe-Arg-NMec (substrate) was added and reacted for 10 minutes, and then 0.1M acetic acid buffer (pH = 4.3) containing 100mM sodium monochloroacetate of ITnIl was added to incubate the reaction. It was stopped.
その後、遊離のアミノメチルクマリンを螢光光度計にて
測定し阻害濃度を求めた。Thereafter, free aminomethylcoumarin was measured using a fluorophotometer to determine the inhibitory concentration.
(結果) 結果は8.5μMであった。(result) The result was 8.5 μM.
第1図は、KBr錠にて測定した生理活性物質3127
のIRスペクトルを示す。
第2図は重ジメチルスルホキシド(DMSO−d、)中
、400MHzで測定した生理活性物質3127の’H
−NMRスペクトルを示す。
第3図は重ジメチルスルホキシド(DMSO−d@)中
、100MHzで測定した生理活性物質3127の”C
−NMRスペクトルを示す。Figure 1 shows the physiologically active substance 3127 measured in KBr tablets.
The IR spectrum of Figure 2 shows the 'H of physiologically active substance 3127 measured at 400 MHz in deuterated dimethyl sulfoxide (DMSO-d).
- Shows the NMR spectrum. Figure 3 shows the “C” of physiologically active substance 3127 measured at 100MHz in deuterated dimethyl sulfoxide (DMSO-d@).
- Shows the NMR spectrum.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1176933A JPH0341089A (en) | 1989-07-07 | 1989-07-07 | Physiologically active substance 3127 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1176933A JPH0341089A (en) | 1989-07-07 | 1989-07-07 | Physiologically active substance 3127 |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0341089A true JPH0341089A (en) | 1991-02-21 |
Family
ID=16022281
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1176933A Pending JPH0341089A (en) | 1989-07-07 | 1989-07-07 | Physiologically active substance 3127 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0341089A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7637057B2 (en) | 2002-04-25 | 2009-12-29 | Aisin Seiki Kabushiki Kaisha | Operating mechanism for an open/close object |
CN102174075A (en) * | 2011-01-31 | 2011-09-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Lipopeptide compound as well as compositions, preparation method and application thereof |
-
1989
- 1989-07-07 JP JP1176933A patent/JPH0341089A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7637057B2 (en) | 2002-04-25 | 2009-12-29 | Aisin Seiki Kabushiki Kaisha | Operating mechanism for an open/close object |
CN102174075A (en) * | 2011-01-31 | 2011-09-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Lipopeptide compound as well as compositions, preparation method and application thereof |
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