• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    An antibiotic complex designated herein as BBM-1675 complex is produced by fermentation of certain novel strains of Actinomadura verrucosospora. The complex may be separated into two major components, BBM-1675A1 and A2, and four minor components, BBM-1675 A3, A4, B1 and B2, and such components exhibit both antimicrobial activity and antitumor activity.
    公开号:SU1344249A3
    申请号:SU843744582
    申请日:1984-05-15
    公开日:1987-10-07
    发明作者:Кониси Масатака；Сайтох Киоитиро；Охкума Хироаки；Кавагути Хироси
    申请人:Бристол-Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to biotechnology, in particular, to the production of antibiotics.
    The aim of the invention is the identification of producer strains and the development of a method for obtaining a new antibiotic with antimicrobial and anti-tumor activity.
    For carrying out the method, the Actinomadura verrucosor spora strain, which is extracted from a soil sample collected in Argentina, is used. The strain was deposited in the American Type Culture Collection under the ATCC number 39334. The mutant strain was obtained from this strain, which was deposited in the same collection under the ATCC number 39638.
    The ATCC strain 39334 is characterized by the following features.
    Cultural and morphological features.
    Forms both substrate and aerial mycelium. Substrate mycelium - long, branched, non-fragmental fibers. Aerial mycelium - short chains of spores are formed monopodially or at the ends of the hyphae; branches in the form of curls, chains of spores are also found near the ends of the hyphae, sporiferous chains contain from 2 to 10 spores in a chain of straight, twisting or hook-shaped form. The spores have a warty surface, from spherical to elliptical shape with rounded or pointed ends measuring 0.5-0.6 X 0.6-1.4 microns. After maturation, each dispute is often separated by an empty shell. Motile spores, sporangia or sclerotic granules are not visible.
    Agar with tryptone and yeast extract (tSP No. O is abundant, flaky-lowering, sedimented, non-pigmented.
    The environment of čapek is moderate, the substrate mycelium is colorless, the aerial mycelium is poor, slightly sery (264) to pale pink (), there is no soluble pigment.
    Agar with glucose and asparagine is a moderate growth, substrate mycelium (263) to deep, yellowish-pink (27), aerial mycelium is absent or very scarce, pale pink (7). Soluble pigment is missing.
    Agar with glycerol and asparagine (ISP H 5) - growth to poor to moderate, substrate mycelium colorless to slightly yellowish-pink (28), aerial mycelium poor, slightly yellowish-pink (28), after 5 months slightly bluish-gray (190. There is no soluble pigment. Agar with inorganic salts and starch (ISP No. .4) - growth is obshtny, substrate. Yellowish mycelium (92), airy mycelium abundant, slightly pink (4) to pinkish-gray (S) There is no soluble pigment.
    Tyrosine agar (ISP No. 7) - moderate growth, substrate mycelium yellowish-white (92), airborne mycelium bad, slightly yellowish-rosy-Vue (28), after 5 months partially bluish-serious (190), Soluble no pigment.
    Nutritional agar is poor to moderate growth.
    Substrate mycelium pale yellow (89), aerial mycelium is absent. soluble pigment is missing.
    Agar with yeast extract and malt extract (ISP No. 2) - growth abundant, substrate mycelium is pale yellow (89), aerial mycelium is poor, white (263). Soluble pigment is missing. Agar with oat flour (ISP № 3) - moderate growth, substrate mycelium colorless to pale pink (7), poor air mycelium, pinkish-white (9) to slightly blue (l90), no soluble pigment.
    Agar with peptone, yeast extract and iron (ISP No. b) is moderate growth, substrate mycelium is colorless, aerial mycelium is absent, there is no soluble pigment.
    Cultural signs were revealed after incubation at 37 ° C for 3 weeks.
    Color and color standard number: Kelly K.L., D, V. Judd: .1 SCC-NBS color-name charts illustrated with Centroid colors. US Dept. of comm, cir.553, Washington, D.C., nov 1975,
    Physiological and biochemical properties: maximum growth at 28-37 C, moderate at 20 and 43 C, does not grow at 10 and 47 ° C (on Bennett agar, pH 5.0-9.5.
    31
    Gelatin liquefies. Starch hydrolyzes. Bottom milk does not coagulate completely peptonized, Melanoid pigment does not form. Nitrates in nitrites do not restore.
    Grows when the concentration of NaCI 5% or less; at 7% - no growth.
    Resistant to lysozyme - growth at 0.01% or less; at 0.1% no growth.
    Utilizes glycerin, arabinose, D-xylose, D-ribose, L-rhamnose, O-glucose, O-fructose, sucrose, cellobiose, trehalose, starch, cellulose, inositol, O-mannitol; does not utilize D (-) - arabinose, D-galactose, O-mannose, L {-) - sorbose, lactose, melibiosis, raffinose, D {+) .- mlytosis, delt it, D-sorbitol, salicin.




    Observations after incubation for 3 weeks.
    Numerous cell wall contains mesodiaminopimelic acid, glycine is absent. Madurosis, glucose and rithosis are present, the main components of menaquinone are identified as MK-9 (Ny) and MK-9 (Hz). Cell wall type lUg.
    The ATCC 39638 ixa mutant strain is characterized by the following;
    Cultural and morphological features.
    Morphology is similar to the original strain. Agar with tryptone and yeast extract (ISP No. O - moderate growth flaky-omitted, sedimented and non-pigmented.
    Czapek's Wednesday - growth is bad. Substrate mycelium is colorless, aerial mycelium is absent or scanty, pinkish-white (9), there is no soluble pigment.
    Agar with glucose and asparagine - growth is bad. Substrate mycelium is colorless, aerial mycelium is absent or very scarce, white. Soluble pigment is missing.
    Agar with glycerol and asparagine (ISP number 5) - moderate growth. Substrate mycelium slightly yellowish-pink (28), aerial mycelium moderate, white to slightly pink (4). Soluble pigment is missing.
    Agar with inorganic salts and starch (ISP No. 4) - moderate growth, substrate mycelium is yellowish-pink (28); aerial mycelium moderate, slightly bluish-gray (190), There is no soluble pigment.
    Tyrosine agar (ISP No. 7) - moderate growth. Substrate mycelium intensively. Yellowish-yellow 26, aerial mycelium moderate, white, slightly pink (.4). Dissolve
    no pigment.
    Nutrient agar is bad growth. Substrate mycelium colorless to
    pale pink (7); aerial mycelium is absent. Soluble pigment is missing.
    Agar with yeast extract and malt extract (ISP No. 2) - abundant growth. The substrate mycelium is intense yellowish-pink (2b); aerial mycelium poor, white to pale pink (7). Soluble pigment is missing.
    Oat flour agar (ISP № З) - bad growth. Substrate mycelium pale yellowish-pink (31); the aerial mycelium is very poor, bright blue-red (184). Soluble
    no pigment.
    Agar with peptone, yeast extract and iron (ISP No. b) - abundant growth. Substrate mycelium is colorless, aerial mycelium and soluble pigment is absent.
    Physiological and biochemical signs.
    It absorbs glycerin, L (+) - arabinose, O-xylose, L-rhamnose, D-glucose, D-fructose, sucrose, cellobiose, trehalose, starch, cellulose, D-mannitol; does not assimilate D (- (- arabinose, 0-ribose, D-galactose, O-mannose, L (- (- sorbose, lactose, melibiose, raffinose, D (1) meliocytosis, dulcite, inositol, O - sorbitol, salicin.
    The remaining properties are similar to the strain ATSS 39334.
    Example 1 Strain Actlncxnadu-ga verrucosospora ATSS 39334 grown and maintained on beveled agar containing,%: malt extract 1; glucose 0,4; yeast extract 0.4; calcium carbonate 0.05, agar 1.6. The culture is used to inoculate a vegetative medium containing,%: soluble starch 3; dry yeast 0,3; KNGRO 0,1; magnesium sulfate heptahydrate 0.05,
    NaCl 0.2, - CaCOj 0.1. pH of the medium before sterilization of 7.0. The seed culture is grown at 32 ° C for 72 hours on a rotating shooter (C 250 rpm); 5 ml of inoculum is transferred to a 500 ml Erlenmeyer flask containing 100 ml of fermentation medium,%: reed molasses 3; corn starch 1; fishmeal 1; CaCOj 0.1; CuS04 5HiO 0.005. pH to sterilization 7.0. The fermentation is carried out at 28 ° C for 6 days on a rotating stirrer.
    When carrying out the process in fermenters, 500 ml of inoculum is transferred to 20-liter can fermenters containing 10 l of fermentation medium. The fermentation is carried out at 32 ° C with an aeration rate of 12 l / min (St.1.2 l of air / min / l of medium) and a stirring speed of 250 rpm.
    After 68-76 hours of fermentation, the maximum antibiotic formation is 0.9 µg / ml.
    When fermentation is carried out in a 200-liter fermentation tank, the process is carried out at 164 rpm of aeration rate of 0.66 l of air / l of medium / min. The pH of the medium gradually rises during the fermentation process and reaches 7.7-7.8 after 170-180 h, the peak of antibiotic activity reaches 1.7 µg / ml.
    Etc. and m 2. p The separation and purification of the antibiotic complex.
    The obtained 3000 l of culture fluid (pH 7.8) is centrifuged to separate the mycelial mass and the supernatant. ; The precipitate obtained is suspended in 1600 l of methanol and the mixture is stirred for 2 hours. Insoluble materials are filtered off, and the methanol extract is concentrated in vacuo to 43 l. The supernatant containing active substances is extracted twice with 1000-liter portions of n-butanol. The n-butanol extracts and concentrated methanol extract are combined and the azeotropic is evaporated by periodically adding water to the aqueous solution (20 liters of oily solid are obtained. The latter is dehydrated in 30 liters of methanol, and insoluble substances
    442496
    filtered off. The methanol extract is concentrated in vacuo to 10 L, then 40 L of ethyl acetate and 30 L of water are added. The mixture is stirred for 30 minutes, the organic layer is separated, dried over sodium sulfate and evaporated in 4 liters. The concentrate is poured into 20 liters of n-hexane-10 san, a pale yellow solid is obtained — crude complex BBM-1675 (90.14 g, activity 55 μg / mg).
    15 20 g of the complex are dissolved in 20 ml of methanol and applied on a Sephadex KH-20 column (5.5 x 85 cm in size). The column is developed with methanol. The active eluates (control with Sta20 phylococcus aureus 209P) are combined, concentrated in vacuo and lyophilized. 4.19 g of semi-purified complex are obtained. Next, a silica gel column chromatography is carried out.
    25 (5.0 x 50 cm) using chloroform and methanol (with an increase in the amount of the latter from 1 to 5% V / V) as eluent. Eluents were combined taking into account antibacterial activity and thin layer chromatography (those) (silica - CHCIj: 5: 1 V / V) and concentrated in vacuo. An almost homogeneous component A is obtained (351 mg yield after evaporation),
    35 elute with 2% methanol in chloroform, and then a mixture of components A, AZ and Ai elute | (507 mg), followed by elution of a mixture of components B (210 mg) with 3% methanol in
    40 hloform. The solid of component A. / is applied to a Sepha-dex LH-20 column (2.0 x 80 cm), which is developed with methanol. The active fractions are concentrated in vacuo to dryness and the resulting solid is crystallized from methanol. Colorless plates of the pure component Af (124 mg) are obtained. I
    5Q Complex BBM-1675 f, A and A are separated by chromatography on a column of Bondarpak C, (SO x 50 cm). The elution was carried out with aqueous acetonitrile and the biologically active eluates were checked with those (silica gel in the reverse phase — CHjCN: H2 = 75:25 V / V). 33 mg A and I8 mg AJ are eluted successively with 20% acetonitrile (301 mg), and
    component Aj is then eluted with 50% acetonitrile.
    The solid containing components B and B is chromatographed on a silica gel C 3.0 x 40 cm column using chloroform and 4% methanol as a developing solvent. The active fractions are combined and evaporated. 7 mg of component B are obtained. Component B was eluted with 5% methanol in chloroform, after evaporation 8 mg of component b was obtained.
    PRI me R 3. Cleaning component A.
    The Glencoe column (2.67 x 75 cm) is filled with a suspension of octadecyl (C / g) silica gel Weaker in the bound phase (particle size 40 µm) in methanol. The column was connected to a HPLC system with pressurized medium and equilibrated with 1.5 l of solvent (4-1.6% acetonitrile, 21.6% methanol, 36.8% 0, W of ammonium acetate). 100.5 mg of the partially purified component A prepared in Example 2 is dissolved in 2 ml of acetonitrile. The resulting sample is passed through the column. The column is quenched with the same eluent and 87 ml fractions are collected. The eluent is monitored at 254 nm and 340 nm. Fractions 55-71 are poured off and extracted twice with 1500 ml of chloroform. Chloroform was evaporated to dryness, to give 89.8 mg of residue (C).
    The Glenco column (1.5x20 cm) is filled with a suspension of 12 g of Woe silica gel 1 t with a particle size of 60-200 µm. The residue (c) was applied to the column in chloroform solution. The column was eluted with 500 ml of a linear gradient of chloroform to 10% methanol in chloroform, and fractions of 20-25 ml were collected. Fractions 6–9 are poured off and evaporated to dryness, yielding 73 mg of residue (D).
    A Glenco column (1.5 x 20 cm) was filled with a suspension of 12 g of Woelm silica gel with a particle size of 63-200 µm in Skellysolve B. The residue (O) was dissolved in 2 ml of chloroform and applied to the column. Chloroform is replaced by 15 ml of Skellysolvo B. A column is eluted with 500 ml of a linear gradient of Skellysolve B to 60% acetone in Skellysolve B and fractions of 26-25 ml are collected. Fractions 19-23 are drained and evaporated to dryness
    Iq 15
    65.6 mg of pure component A are obtained.
    Component A is white to pale yellow crystals. Melting point 156-158 ° C (with decomposition).
    Elementary analysis: C - 52.17%, H - 6.15%; N - 4.63%; S - 9.09%, O - 27.96%.
    UV absorbance spectrum (Varian UV, Saga 219, solvent methanol, concentration 0.01356 g / l):
    I max. (nm) Absorption
    ability

    12.4 shoulder 25.1 25.5
    Optical rotation (solvent - СНС1з): Г, - 207 (С 0.0351), СЛГ - 191 (С 0.5, CHCl3).
    By thin layer chromatography on silica gel (solvent system CHClj: CHjOH - 5: 1 V / V) Ry 0.74; on silica gel in reverse phase (CHjCN: HjO - 75:25 V / V) Ry 0.18,
    Main absorption bands (KBG): 985.1015, 1070, 1110, 1150, 1210, 1250, 1308, 1380, 1405, 1446, 1520, 1592, 1608, 1668, 1715, 2920.2960, 3360, 3440 cm. Mol.m. 1248.
    Soluble in chloroform, ethyl acetate, acetone, ethanol, and methanol; slightly soluble in benzene and water; insoluble in n-hexane and carbon tetrachloride.
    Gives a positive reaction with ferric chloride, Ehrlich and Tollen reagents; negative reaction in Sakaguchi's experiments. snegnidrinom and antronom.
    It has antibacterial activity against various bacteria and fungi; induces prophage in lysogenic bacteria; inhibits the growth of P-388 leukemia, L-1210 leukemia B16 melanoma and pulmonary Lewis pulmonary carcinoma (in mice).
    Cleaning component A.
    The Glencoe column (inner diameter 2.65 cm) is filled with a suspension of octadecyl (C ") Baker silica gel in
    the bound phase in methanol (particle size 40 µm}. The column is attached to the HPLC system at medium pressure and equilibrated with 1.5 liters of eluent (50% acetonitrile, 20% methanol, 30% 0.1 M ammonium acetate). 76.9 mg partially The purified component A2 (prepared according to Example 2) is dissolved in 2 ml of acetonitrile and a sample is prepared. The latter is applied to a column, which is eluted with the same eluent. 87 ml of fractions 31-738 are collected, extracted twice with 500 ml of chloroform. evaporated to dryness. 65.8 mg of the homogeneous component is obtained.
    Component A has the appearance of white crystals; soluble in chloroform, ethyl acetate, acetone, ethanol, methanol; slightly soluble in benzene and water; insoluble in n-hexane and carbon tetrachloride. Gives a positive reaction with ferric chloride (W), Ehrlich and Tollen reagents; negative reaction in Sakaguchi’s experiments, using ninhydrin and anthron,
    Melting point 147-149 ° C, Optical rotation angle Co () 179.4 (C 0.5, CHC1e), mole, m. l, 1248.
    Elementary composition: From 52.71%; H 5.94%; N 3.94%; S 9.39%; h About 28.01%.



    125-127123-126
    -161-176
    С - 54.55% С-54.65%
    H - 6.46N - 6.29%
    And - 3.73% - 3.51%
    S - 7.49S - 8.07%
    O - 27.77% O - 27.48%
    253 (286) 253 (257)
    0.71 (those on silica gel, the solvent system is chloroform: methanol 5: 1 V / V); R 0.21 (reverse phase silica gel, acetonitrile: water - 75:25 V / V).
    UV absorption (methanol, € 02052 t / l);
    I max, 320
    282.
    252
    214
    (nm) Absorbency 12.2
    16.3
    26.2 25.8
    IR spectrum (KBG): 950, 1015, 1070, 1100, 1155, 1213, 1250, 1313, 1375, -1405.1450, 1520, 1595, 1610, 1735, 2940, 2980, 3440.
    Has antimicrobial activity against various bacteria and fungi; induces prophag in lysogenic bacteria; inhibits the growth of leukemia P-388, leukemia L-1210, B16 melanoma, pulmonary Lewis carcinoma (on the neck).
    The table shows the physicomechanical properties of the components A, A, By, Br.
    159-161
    156-159
    -171
    -122
    253 (225) 248 (212)
    All components give a positive reaction with ferric chloride (W), with Ehrlich and Tollek reagents and a negative reaction in the Sakaguchi experiments, with ninhydrin and anthrone.
    They have antimicrobial activity against various bacteria and fungi (staphylococcus, microbacteria, escherichia, Klebsiella, pseudomonads, various Candida species, etc.). Prophage is induced in lysogenic bacteria, Aj components, and inhibit the growth of P-388 leukemia.
    The following example illustrates a method for producing an antibiotic complex using an Actino-, madura verrucosospora LTCC 39638 culture.
    PRI me R A. A vegetative medium containing 2% soluble collapse is small, 1% glucose, 0.5% yeast extract, 0.5% NB-amine type A and 0.1% calcium carbonate, pH prior to sterilization 7 , 0, seeded with ATCC 39638 strain. Seeding is incubated at 32 ° C. for 4 days on a rotating stirrer (250 rpm). Then, 5 ml of the obtained culture was transferred to a 500 ml Erlenmeyer flask with 100 ml of fermentation medium (3% cane molasses, 1% corn starch, 1% fish meal, 0.005% copper sulfate pentahydrate, 0.05% magnesium sulfate heptahydrate,
    0.1% calcium carbonate, pH sterilization 7.0).
    Fermentation is carried out at 28 ° C for 7 days on a rotating
    131344249
    with agitator. 1.5 μg / s of 2% methanol in benzene, / ml of antibiotic complex are obtained. The fractions containing the homogeneous com-EXAMPLE 5. Obtained according to the “A”, are evaporated in vacuum up to 4 with the fermentation broth (3000 l. Ha. The obtained dense substance
    pH 7.6} is divided into a mycelial cake and a layer ()).
    The mycelial cake is extracted with 2000 L of methanol for 1 hour and filtered.
    The active substances contained. in the supernatant, extracted with 1800 l of n-butanol.
    The methanol and n-butanol extracts are combined and concentrated azeotropically with periodic addition of water (20 liters of J to the aqueous solution, and an oily solid precipitates. The mixture is shaken 3 times with 20 liters (for each shaking of ethyl acetate. The extracts are combined, filtered and evaporated to 4 liters. The concentrate is mixed with 30 liters of n-hexane with stirring to give a pale yellow solid (81.7 g, activity 59 µg / / mg). The crude complex (20 g) is dissolved in 20 ml methanol and nano- t on a column of Sephadex H-20 (5.5 x x 85 cm). Colo ku exhibit methanol elution monitored by bioassay using Staphylococcus aureus 209R
    The active eluents are combined, concentrated in vacuo and lyophilized. 4.86 g of complex are obtained, activity 203 µg / ml. The resulting material is chromatographed on a silica gel column (3.0x70 cm) using chloroform and an amount of methanol increasing from 1 to 5% as a developer. The eluates were tested for antibacterial activity by TLC, then coagulated and concentrated in vacuo.
    The concentrate was eluted with 2% methanol in chloroform to obtain 425 mg (after evaporation) of component A with an activity of 960 µg / ml, and then 732 mg of a mixture of components Aj, AZ and A (activity 340 µg / mg), followed by elution with 3% with methanol in chloroform of the complex of components B and Bj (200 mg, activity 190 μg / / mg).
    Component A obtained above is rechromatographed on a silica gel column (2.2x44 cm) using
    crystallized from 10 ml of methanol. Colorless crystals of component A are obtained (197 mg, activity 1000 μg / ml).
    Complex A2, -A, and A (537 mg) were separated by chromatography on a column of Bendapac C, (2.0 x X 42 cm). Eluted with aqueous acetonitrile and biologically active eluates.
    checked by TLC (Merch, reverse phase silica gel 75: 25 V / V).
    0
    0
    0
    Components A (45 mg, activity 410 μg / mg) and AZ (19 mg, activity 300 μg / mg) are eluted with 20% acetonitrile and then with 50% acetonitrile. Component A (203 mg) is eluted . The fractions of component A of the crystal are talized from a mixture of chloroform-n-hexane. Colorless rods are precipitated (70 mg, activity 290 μg / mg).
    The dense substance containing components B and Br is chromatographed on a silica gel column (3.0x40 cm using chloroform and methanol as elution solution. Active fractions eluted with 4% methanol in chloroform are combined and evaporated. 7 mg of pure component is obtained B with an activity of 180 µg / mg Component B was eluted with 5% methanol in chloroform and after evaporation 8 mg of component B. with an activity of 140 µg / mg was obtained.
    The use of the proposed method and producer strains makes it possible to obtain a group of new antibiotics with a broad antimicrobial spectrum, inducing prophages in lysogenic bacteria and possessing an antitumor effect on leukemia, melanoma, pulmonary carcinoma, and Lewis.
    50
    权利要求:
    Claims (2)
    [1]
    1. A method for producing components A, A2, Az, Ai, B or Bj. antibiotic: BBM-1675 complex with antimicrobial and antitumor effects, namely, Actinomadura verrucosospoga strain ATCC 39334 or Actinomadura strain
    151
    verrucosospora ATCC 39638 is cultivated in a liquid nutrient medium containing sources of carbon, nitrogen and mineral salts under deep aerobic conditions for 68 hours to 7 days at an aeration rate of 0.667 to 1.2 liters of air / min / l of fermentation medium, the mycelium is then separated from the fermentation liquid, extracted, separately with organic solvents, the extracts are combined, concentrated, the resulting semi-purified complex is separated by chromatography, the compound is eluted
    4A24916
    Complexes are complexed with organic solvents and purify the target products.
    I
    [2]
    2. Actinomadug verrucosospora ATCC 3933D strain of actinomycete and Actinnomadura verrucosospora ATCC S9638 (American Type Cul-10 ture col lection) actinomycete strain used to obtain components A, A2, Aj, A4, B, or Bj of the antibiological complex, Lexa VVM -1675 with antimicrobial and antitumor effects 15.
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    ATA160984A|1991-05-15|
    DE3418023A1|1984-11-22|
    AU2779184A|1984-11-22|
    ES532476A0|1986-09-16|
    FI81114C|1990-09-10|
    DK163127B|1992-01-20|
    FI841906A|1984-11-17|
    HUT37168A|1985-11-28|
    ZA843591B|1985-02-27|
    IE841200L|1984-11-16|
    引用文献:
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    US4195079A|1979-01-31|1980-03-25|Pfizer Inc.|New polycyclic ether antibiotic|
    JPS6254320B2|1980-02-15|1987-11-13|Kaken Pharma Co Ltd|
    GR78648B|1982-07-26|1984-09-27|Bristol Myers Co|
    US4539203A|1984-11-13|1985-09-03|Warner-Lambert Company|CL-1577D And CL-1577E antibiotic/antitumor compounds, their production and use|GR78648B|1982-07-26|1984-09-27|Bristol Myers Co|
    IL79519D0|1985-08-27|1986-10-31|Bristol Myers Co|Bbm-1675c and d antitumor antibiotics|
    US4837206A|1987-04-29|1989-06-06|Bristol-Myers Company|Esperamicin derivatives|
    US4996305A|1988-02-29|1991-02-26|American Cyanamid Company|Process for producing the antibiotic and antitumor agents LL-E33288.epsilon.ε-Br|
    CA2027601A1|1989-11-06|1991-05-07|Koko Sugawara|Antitumor antibiotic bu-3983t|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US49523183A| true| 1983-05-16|1983-05-16|
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