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USRE30451E - Novel process for producing antibiotics bleomycin - Google Patents

Novel process for producing antibiotics bleomycin Download PDF

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Publication number
USRE30451E
USRE30451E US06/041,996 US4199679A USRE30451E US RE30451 E USRE30451 E US RE30451E US 4199679 A US4199679 A US 4199679A US RE30451 E USRE30451 E US RE30451E
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United States
Prior art keywords
sub
bleomycin
diaminopropane
amino
aminopropyl
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Expired - Lifetime
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US06/041,996
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English (en)
Inventor
Hamao Umezawa
Kenji Maeda
Tomohisa Takita
Yuya Nakayama
Akio Fujii
Nobuyoshi Shimada
Hideo Chimura
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Microbial Chemistry Research Foundation
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Microbial Chemistry Research Foundation
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Priority claimed from JP1077469A external-priority patent/JPS4832354B1/ja
Priority claimed from JP44087589A external-priority patent/JPS4832355B1/ja
Application filed by Microbial Chemistry Research Foundation filed Critical Microbial Chemistry Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C07K9/003—Peptides being substituted by heterocyclic radicals, e.g. bleomycin, phleomycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • This invention relates to a novel process for producing antibiotics bleomycins. More particularly, the invention pertains to a novel process for producing antibiotics bleomycins by inoculating and aerobically culturing in a nutrient source-containing medium a bleomycin-producing strain belonging to the actinomyces, wherein the culture is effected in the presence of an amino compound having at least one ##STR2## group and at least one basic group selected from amino, imino, guanidino, amidino and sulfonium groups and nitrogencontaining cyclic compounds, or in the presence of a compound convertible in the culture liquor to such amino compound as mentioned above, thereby selectively producing a known or novel bleomycin component corresponding to the above-mentioned amino compound or to an amino compound derived from the above-mentioned compound, and then the known or novel bleomycin is recovered by known means from the culture medium.
  • Bleomycins are anti-tumor antibiotics discovered by Umezawa et al. and are obtained in such a manner that a bleomycin-producing strain belonging to the actinomyces Streptomyces verticillus (e.g., ATCC No. 15003) is aerobically cultured with stirring in a nutrient medium chloride, potassium phosphate, zinc sulfate, copose), glucose, soybean power, corn steep liquor, sodium chloride, potassium phosphate, zinc sulfate, copper sulfate, etc., and the resulting bleomycin is isolated and recovered in the form of hydrochloride or sulfate from the culture liquor by adoption of such a means as using ion-exchange resin.
  • a bleomycin-producing strain belonging to the actinomyces Streptomyces verticillus e.g., ATCC No. 15003
  • a bleomycin-producing strain belonging to the actinomyces Streptomyces verticillus e
  • bleomycin components contain A 1 , A 2 , A' 2 , A 3 , A 4 , A 5 , A 6 , B 1 , B 2 , B 3 , B 4 , B 5 , B 6 and the like components (hereinafter referred to as the bleomycin components) and, when further subjected to copper removal treatment, these bleomycin components are obtained as white powders.
  • Bleomycin has been known as a general term for antibiotics containing these components (British Pat. No. 1,038,242).
  • the present inventors studied the structures of bleomycins to find that the bleomycin components have a structure represented by the formula (I) set forth below, ##STR3## wherein R represents any of the formulas ##STR4## where X, X', R 1 , R 2 , R 3 R 4 and R 5 are as hereinafter defined, and that R in the formula varies, for example below, depending on the kind of bleomycin components. ##STR5##
  • the inventors further repeated the studies to find that when various amino compounds corresponding to the side chain portion R in the above-mentioned formula (I), or amino compounds convertible during the culture to amines corresponding to the side chain portion, are added to the culture liquors if bleomycin-producing strains, desired bleomycin compounds can be obtained in favorable yields, and that when certain kinds of amino compounds are added, novel bleomycins different from the aforesaid bleomycins are produced and, when separated from the culture liquors and are purified, the novel bleomycins can be recovered in high yields.
  • the present inventors have accomplished the present invention.
  • n' an integer of 0-8,
  • R 6 , R 6' , R 6" , R 7 , R 7' , R 8 , R 8' , R 8" , R 8'" , R 9 , R 9' , R 10 , R 10' , R 10" H, alkyl group.
  • the dotted line in the formula shows that hydrogen atom on carbon chain may be substituted at any position of the alkyl group.
  • Typical examples of the amino compounds represented by the above-mentioned general formulas (1)-(5) and of the compounds convertible to said amino compounds during the culture are set forth below.
  • 3-aminopropyl-dimethylsulfonium bromide or 3-amino-3-carboxypropyl-dimethylsulfonium chloride for example, is added as the amino compound to a nutrient medium and such bleomycin-producing strain as Streptomyces verticillus is cultured in said medium, the productivity of bleomycin A 2 is enhanced to increase the content (percent) of bleomycin A 2 among the whole bleomycins present in the culture liquor.
  • the addition of hydrochloride of agmatine increases the content (percent) of bleomcyin B 2
  • the addition of 1,4-diaminobutane increases the content (percent) of bleomycin A 2 '
  • the addition of spermidine increases the content of bleomycin A 5 .
  • the addition of spermine results not only in the production of bleomycin A 6 of corresponding side chain but also in the production of bleomycin A 5 having in the side chain spermidine which has been formed from the spermine during the culture.
  • the addition of spermine results chiefly in the production of bleomycin A 5 .
  • 1,2-diaminoethane or 1,3-diaminopropane results in the production of novel 2-aminoethylamino-bleomycin or 3-aminopropylamino-bleomycin.
  • such a chain polyamino compound as N,N-bis(3-aminopropyl)-methylamine chiefly produces such novel bleomycin as 3-(N-methyl-N-3-aminopropyl)-aminopropylamino-bleomycin having the same side chain as that of the compound added and, in addition, entrains a low molecular weight amine, which has been formed from said additive during the culture to by-produce 3-N-methylaminopropylamine-bleomcyin.
  • the amino compounds to be added are used either as they are or in the form of inorganic acid salts, but the concentrations thereof in the culture liquor vary depending on their kind. In general, the concentration of the amino compounds is within the range of 0.1-45 milligram per milliliter of the culture liquor.
  • a medium which is composed mainly of carbohydrates and nitrogen-containing organic substances such as millet jelly, glucose, starch, soybean powder, corn steep liquor, etc., and which has been incorporated with small amounts of inorganic substances such as, for example, potassium phosphate, copper sulfate, zinc sulfate, sodium chloride, nitrates, etc.
  • the carbohydrates and the nitrogen-containing organic substances are use in an amount of 0.1-10 percent by weight and the inorganic salts are used in an amount of 0.01-5 percent by weight, based on the total weight of the medium.
  • Streptomyces verticillus or a bleomycin-producing strain among the variants thereof, such as for examples, the strains ATCC 15003 or ATCC 21678, is aerobically cultured at 25°-30° C. and pH of 5.0-9.0 for 50-300 hours according to ordinary procedures, which have been shown in the literature, "H. Umezawa et al., New Antibiotics Bleomycin A and B, J. Antibiotics, Ser. A, 1966, pp. 200-209.” Thereafter, the culture liquor is subjected to treatment with ordinary procedures, which have been shown in the literature, "H. Umezawa et al., Purification of Bleomycins, J. Antibiotics, Ser. A, 1966, pp.
  • the culture liquor is filtered and the filtrate is adsorbed on, for example, a cation exchange resin having a reactive group, such as a carboxyl group, and is then eluted with an aqueous hydrochloric acid solution.
  • the cation exchange resin includes, such as for example, Amberite IRC-50 and Duolite CS-101 (tradename for acidic cation exchange resin containing carboxylic acid group, the former is manufactured by Rohm & Haas Co., U.S.A., the latter by Chemical Process Co., U.S.A.).
  • the elute is subjected successively to the steps of adsorption on active carbon, elution with aqueous acetone-hydrochloric acid solution, alumina adsorption, aqueous methanol elution, adsorption on Sephadex (tradename for a dry, insoluble powder composed of microscopic beads which are synthetic, organic compounds derived from the polysaccharide dextran; manufactured and sold by Pharmacia Fine Chemicals Inc.) and elution with distilled water, whereby a bleomycin hydrochloride powder is obtained.
  • CM Sephadex tradename for an acidic ion-exchanger composed of carboxymethyl-Sephadex manufactured by Pharmacia Fine Chemicals Inc.
  • the eluate is adsorbed on active carbon and is subjected to the steps of water-washing and elution with aqueous acetone-hydrochloric acid solution, whereby a pure bleomycin component can be obtained.
  • a bleomycin component has sufficiently selectively been produced in the culture medium, the step of separation using CM Sephadex may be omitted.
  • Bleomycins have a property to chelate with copper and are obtained as a blue powder from the culture liquor, but the copper can be removed by effecting the treatment of copper removal in any of the extraction or purification step.
  • the content of new (or main) bleomycin was measured in such a manner that the bleomycin (mixture of individual components) obtained by the culture and purification in each of the examples shown previously was separated by use of CM-Sephadex and was then subjected to ultraviolet absorption spectrophotometry.
  • the potency was measured according to biological assay, using copper-free bleomycin A 2 hydrochloride (potency 940 mcg/mg) as a standard substance and Mycobacterium tuberculosis 607 (upper) and Bucillus subtilis (lower) as a test microorganism.
  • Solvent 10:9:1 mixture of methanol--10 percent ammonium acetate--10 percent aqueous ammonia solution.
  • Solvent 10 percent aqueous ammonium chloride solution.
  • Novel bleomycins obtained according to the present invention show no definite melting point, decomposition point or boiling point and inhibit gram positive and negative bacteria and have antitumor activity.
  • Said bleomycins are soluble in water and aqueous methanol.
  • Said bleomycins form salts with acids and chelate with copper.
  • Said bleomycins give positive reaction in Pauly, Ehrlich, Dragendorff and permanganate reactions but give negative reaction in Molish, Biuret, Elson-Morgan, Maltol, Fehling, Tollens, Anthrone and ferric chloride reactions.
  • Said bleomycins exhibit, in infrared region, adsorption zone at the following wave numbers: 1,040-1,075 cm -1 , 1,710-1,735 cm -1 , 1,625-1,680 cm -1 , 2,910-2,940 cm -1 , 3,200-3,400 cm -1 .
  • Said bleomycins are further characterized by the facts that their acid hydrolysis give L-threonine, ⁇ -amino- ⁇ -(4-amino-6-carboxy-5-methyl-pyrimidine-2-yl)propionic acid, 4-amino-3-hydroxy-2-methyl-n-valeric acid, ⁇ -hydroxyhistidine, L- ⁇ -aminoalanine, L-glucose, 3-o-carbamoyl-D-mannose, 2'-(2-aminoethyl)-2,4'-bithiazole-4-carboxylic acid and each amino compound corresponding to side chain portion.
  • the novel bleomycins obtained according to the present invention are similar to the known bleomycin components in appearance and infrared and ultraviolet absorption curve, but are obviously different therefrom in potency (mcg/mg) and Rf values. Further, what is worthy of special mention is that when these novel substances are hydrolyzed with strong acid and the hydrolyzates are subjected to gas chromatography, the amino compounds used as additives for the culture, or amino compounds formed during the culture, are detected and it has been confirmed that they have side chains corresponding to the amino compounds added or to the amino compounds formed during the culture.
  • bleomycin A 5 which is strong in anti-tumor property and less in toxicity, can selectively obtained. Further, it has become possible to obtain such novel bleomycins as 3-(1-phenylethyl)-aminopropylamino-bleomycin which are excellent in effect and less toxicity.
  • bleomycins obtained according to the present invention have a more safety and excellent anti-tumor effect as compared with any other conventionally known anti-tumor substances
  • the life-prolongation effect of bleomycins obtained according to the present invention is compared with that of mytomycin C as a control medicine on mice inoculated with the ascites type of the Ehrlich carcinoma below.
  • mice of ICR/JCL strain ( ⁇ 5 weeks old, five for one group) are inoculated with Ehrlich ascites carcinoma cells in a dose of 2 millions/mouse.
  • Bleomycin ranging from 25 mg/kg to 0.19 mg/kg is administered intraperitoneally once a day for 10 days starting from 2 hours after the inoculation, the death is observed everyday up to 50 days after the inoculation and body weights are measured every 5 days.
  • LD 50 is calculated by Behres-Karber's method from the group poisoned at high dose levels.
  • a survival percentage at each dose level is obtained by assuming the average number of survival days observed with the control group administered with physiological saline water to be 100 percent, and those having survived for such periods as 200 percent of that of the control or longer are regarded as effective.
  • the maximum dose level at which they survive for such period as 100 to 200 percent of the survival days for the control is signified by ED 50 .
  • bleomycins show high index number indicating a large difference between a measure amount showing toxicity and that showing life-prolonged effect as compared with mytomycin C used as a control medicine. Therefore, it can be said that bleomycin can be used far more safely and is more expectable in the anti-tumor effect than any other conventionally known anti-tumor substances.
  • To a medium having a composition of 6.4 percent of millet jelly, 0.5 percent of glucose, 3.5 percent of soybean powder, 0.75 percent of corn steep liquor, 0.3 percent of sodium chloride, 0.1 percent of potassium secondary phosphate, 0.05 percent of zinc sulfate, 0.01 percent of copper sulfate, 0.2 percent of sodium nitrate and 0.01 percent of Toho No. 1 (tradename for a surface active agent composed of polyoxyethylene manufactured by Toho Chemical Industry Co. Ltd., Japan) was added 3-amino-propyl-dimethylsulfonium bromide hydrobromate in a proportion of 0.4 mg/ml to adjust the pH of the medium to 6.5.
  • bleomycin-containing fractions were collected and concentrated to dryness to obtain 195 mg of bleomycin hydrochloride (potency 650.7 mcg/mg, total potency 172 mg). The yield from the culture filtrate was 30.5 percent.
  • CM-Sephadex method in the following examples.
  • the resulting residue was dissolved in 4 ml of an 80 percent aqueous methanol solution and was charged into a column packed with 70 ml of neutral alumina, followed by elution with an 80 percent aqueous methanol solution. Subsequently, bleomycin-containing fractions were collected and concentrated to dryness, and the residue was dissolved in 2 ml of water and was charged into a column packed with 20 ml of sephadex G-25 (tradename of Pharmacia Fine Chemical Inc., one kind of Sephadex), and then elution was effected by use of distilled water.
  • sephadex G-25 tradename of Pharmacia Fine Chemical Inc., one kind of Sephadex
  • the resulting bluish green bleomycin-containing fraction was recovered, was suspended in a 0.02 M aqueous ammonium chloride solution, was added to a column packed with 20 ml of CM-Sephadex C-25 and was then eluted with a 0.1 M aqueous ammonium chloride solution.
  • the resulting fraction containing the desired substance was taken up and was passed through a column packed with 5 ml of active carbon to adsorb the desired substance, which was then eluted with a 1:1 mixture of acetone-aqueous 0.01 N hydrochloric acid solution. Subsequently, the eluate was concentrated to dryness to obtain 35 mg of 2-aminopropyl-amino-bleomycin (potency 2,173 mcg/mg, total potency 76.1 mg). the yield from the culture filtrate was 11.25 percent.

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  • Chemical & Material Sciences (AREA)
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  • Genetics & Genomics (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Molecular Biology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US06/041,996 1969-02-15 1979-05-24 Novel process for producing antibiotics bleomycin Expired - Lifetime USRE30451E (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP49-10774 1969-02-15
JP1077469A JPS4832354B1 (xx) 1969-02-15 1969-02-15
JP49-87589 1969-11-04
JP44087589A JPS4832355B1 (xx) 1969-11-04 1969-11-04

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US1042170A Continuation-In-Part 1969-02-15 1970-02-11
US00291079A Reissue US3846400A (en) 1969-02-15 1972-09-21 Novel process for producing antibiotics bleomycin

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AT (1) AT295743B (xx)
BE (1) BE745926A (xx)
BG (1) BG17632A3 (xx)
CA (1) CA923055A (xx)
CH (1) CH545343A (xx)
CS (1) CS150904B2 (xx)
DE (1) DE2006446C3 (xx)
DK (1) DK123605B (xx)
ES (1) ES376555A1 (xx)
FI (1) FI46178C (xx)
FR (1) FR2034552B1 (xx)
GB (1) GB1292081A (xx)
IL (1) IL33879A (xx)
NL (1) NL147187B (xx)
NO (1) NO132875C (xx)
PL (1) PL80837B1 (xx)
RO (1) RO54829A (xx)
SE (1) SE360677B (xx)
YU (1) YU36389B (xx)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3247199A1 (de) * 1981-12-29 1983-07-07 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai, Tokyo Aminopropylaminobleomycinderivate und verfahren zu ihrer herstellung
US4472304A (en) 1981-12-29 1984-09-18 Nippon Kayaku Kabushiki Kaisha (Amido)N-substituted bleomycins, salts thereof and process for preparation thereof
US4808703A (en) 1983-06-27 1989-02-28 Zaidan Hojin Biseibutsu Kagaku Kenku Kai Novel 3-(4'-aminobutylamino) propylaminobleomycin derivatives

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1292081A (en) 1969-02-15 1972-10-11 Zaidan Hojin Biseibutsu Process for producing bleomycin antibiotics
US3846400A (en) * 1969-02-15 1974-11-05 Microbial Chem Res Found Novel process for producing antibiotics bleomycin
JPS5739751B2 (xx) * 1972-03-03 1982-08-23
FR2199456A2 (en) * 1972-09-20 1974-04-12 Microbial Chem Res Found Bleomycin derivs
FR2199455A2 (en) * 1972-09-20 1974-04-12 Nippon Kayaku Kk Bleomycin derivs
GB1540466A (en) * 1975-10-29 1979-02-14 Meiji Seika Kaisha Antibiotic polypeptides sf-1771 and sf-1881-b and production thereof
CA1090728A (en) * 1976-02-04 1980-12-02 Eli Lilly And Company Antibiotic a-7413 mixture comprising factors a,b,c and d and a process for producing it
US4246400A (en) * 1979-07-13 1981-01-20 Bristol-Myers Company Tallysomycin compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3846400A (en) * 1969-02-15 1974-11-05 Microbial Chem Res Found Novel process for producing antibiotics bleomycin
DE2006446C3 (de) 1969-02-15 1978-08-31 Microbial Chem Res Found Verfahren zur Herstellung von Bleomycin-Antibiotika sowie Bleomycine mit strukturell abgewandelter Seitenkette

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3846400A (en) * 1969-02-15 1974-11-05 Microbial Chem Res Found Novel process for producing antibiotics bleomycin
DE2006446C3 (de) 1969-02-15 1978-08-31 Microbial Chem Res Found Verfahren zur Herstellung von Bleomycin-Antibiotika sowie Bleomycine mit strukturell abgewandelter Seitenkette

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Journal of Antibiotics, Aug. 1978, pp. 801-804. *
Takita et al., J. of Antibiotics (Tokyo), 22, 237-239, (1969). *
Takita et al., Prog. in Antimicro. Anticancer Chemothr., 2, 1031-1036, (1970). *
Umezawa, Asian Med. J., 13, 190-209, (1970). *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3247199A1 (de) * 1981-12-29 1983-07-07 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai, Tokyo Aminopropylaminobleomycinderivate und verfahren zu ihrer herstellung
US4472304A (en) 1981-12-29 1984-09-18 Nippon Kayaku Kabushiki Kaisha (Amido)N-substituted bleomycins, salts thereof and process for preparation thereof
US4537880A (en) 1981-12-29 1985-08-27 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Aminopropylaminobleomycin derivatives and process for preparation thereof
US4568490A (en) 1981-12-29 1986-02-04 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Aminopropylaminobleomycin derivatives and process for preparation thereof
US4808703A (en) 1983-06-27 1989-02-28 Zaidan Hojin Biseibutsu Kagaku Kenku Kai Novel 3-(4'-aminobutylamino) propylaminobleomycin derivatives

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SE360677B (xx) 1973-10-01
IL33879A0 (en) 1970-04-20
IL33879A (en) 1973-05-31
ES376555A1 (es) 1972-06-16
BG17632A3 (bg) 1973-11-10
CA923055A (en) 1973-03-20
NO132875B (xx) 1975-10-13
CH545343A (de) 1973-12-15
FR2034552A1 (xx) 1970-12-11
DE2006446A1 (xx) 1970-10-22
FR2034552B1 (xx) 1974-01-11
CS150904B2 (xx) 1973-09-17
BE745926A (fr) 1970-07-16
DK123605B (da) 1972-07-10
YU35870A (en) 1981-11-13
NL7002104A (xx) 1970-08-18
DE2006446C3 (de) 1978-08-31
DE2006446B2 (de) 1977-09-29
AT295743B (de) 1972-01-10
YU36389B (en) 1983-06-30
FI46178B (xx) 1972-10-02
RO54829A (xx) 1973-07-20
GB1292081A (en) 1972-10-11
PL80837B1 (en) 1975-08-30
NL147187B (nl) 1975-09-15
FI46178C (fi) 1973-01-10
NO132875C (xx) 1976-01-21

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