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CA2004304A1 - Angucyclinones from streptomycetes, a process for the preparation thereof and the use thereof - Google Patents

Angucyclinones from streptomycetes, a process for the preparation thereof and the use thereof

Info

Publication number
CA2004304A1
CA2004304A1 CA002004304A CA2004304A CA2004304A1 CA 2004304 A1 CA2004304 A1 CA 2004304A1 CA 002004304 A CA002004304 A CA 002004304A CA 2004304 A CA2004304 A CA 2004304A CA 2004304 A1 CA2004304 A1 CA 2004304A1
Authority
CA
Canada
Prior art keywords
compound
formula
preparation
nutrient solution
dsm
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.)
Abandoned
Application number
CA002004304A
Other languages
French (fr)
Inventor
Joachim Wink
Peter Hammann
Heinz Kluge
Alfred Roth (Deceased)
Irvin Winkler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Publication of CA2004304A1 publication Critical patent/CA2004304A1/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C12P15/00—Preparation of compounds containing at least three condensed carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Zoology (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE:

New angucyclinones from Streptomycetes, a process for the preparation thereof and the use thereof New angucyclinones with a therapeutic action can be prepared with the aid of a strain of the genus Streptomyces.

Description

~0~4304 HOECHST ARTIENGESELLSCHAFT HOE 88/F 338 Dr. RH/PP

Description New angucyclinones from Streptomycete~, a process for the preparation thereof ~nd the u~e thereof It is known that Streptomyces spec. synthesizeæ under conventional culture conditions an angucyclinone with the name ochromycinone tBowie J.H., Johnson A.N. Tetrahedron Letters I6, 1449 (1967)~
:' `'`' It has now been found, surprisingly, that Streptomyces spec. DSM 4769 produces new angucyclinones.

Hence the invention relates to~

1. A compound of the formula I
~ . .,:

in which a) Rl and R2 are hydroxyl, ; ;~
b) Rl is an oxo group and R2 is hydroxyl or c) Rl and R2 are an oxo group. ~.~
, ,' , " . ,',: .' . . . -2. A process for the preparation of the compound of the -~
formula I, which comprises cultivation of Strep-. ~:
tomyces spec. DSM 4769 until the compound of the formula I accumulates in the culture medium, and -i~olation of the compound where appropriate.
3. The use of the compound of the formula I as a sub~tance having therapeutic activity. ;`~ ~-The invention is described in detail hereinafter, especially in its preferred embodiments. The invention is ,-. . ~ :: . . .:
'''~,' '.'',..",''''~
:: :: . , :
'' .,'"'~"., ". .~

2U~4304 :

furthermore defined in the patent claims. The compound of the formula I can be prepared with the aid of Streptomyces spec. DSM 4769. The strain was deposited on Aug. 26, 1988, at the Deutsche Sammlung von Mikroorganismen und Zellkulturen (German Microorganism and Cell Culture Collection) under the stated number in accordance with the conditions of the Budapest Treaty.
. ,. .: ~: . . :~
Streptomyces spec. DSM 4769 has the following ~ -characteristic features~
~ . ~
Spore color: red Spore chain: close spirals Spore surface: smooth Melanin production: positive ~'' It is also possible in place of Streptomyces spec.
lS DSM 4769 to use its mutants and variants as long as they are in fact able to prepare the compound of the formula I. Mutants of this type can be generated in a manner known per se by physical means, for example irradiation such a8 with ultraviolet or X-ray6, or chemical mutagens such as, for example, ethyl methane sulfonate (EMS), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or 2-hydroxy-4-methoxybenzophenone (MOB).

Suitable and preferred as sources of carbon for the aerobic fermentation are assimilable carbohydrates and sugar alcohols such ns glucose, lactose or D-mannitol, as well as carbohydrate-containing natural product such as malt extract. Suitable and preferred nitrogen-containing nutrients aret amino acids, peptides and proteins a8 well a8 the degradation products thereof, such a8 peptones or tryptones, also meat extracts, milled seeds, for example of corn, wheat, beans, soybean or the cotton plant, dis-tillation re~idues from the production of alcohol, meat meals or yeast extracts, a8 well as ~mmonium salts and nitrates. The nutrient solution can additionally contain, for example, chlorides, carbonates, sulfates or .. ~
.: .... :,.,~ . i .
' ''' '' '"'''' :;, ' ..'."......

200~304 phosphates of the alkali metals or alkaline earth metals, iron, zinc and manganese as additional inorganic salts.

The production of the compound of the formula I
takes place especially well in a nutrient solution which contains glycerol in concentrations of 0.5 to 6 ~, preferably 2 to 4 %, as well as soybean meal in con-centrations of 0.1 to 4 %, preferably 0.5 to 2 %, in each case based on the weight of the total nutrient solution.

The fermentation is carried out aerobically, that is to say, for example, submerged with shaking or stirring in shaken flasks or fermenters, where appropriate introducing air or oxygen. The fermentation can be carried out in a temperature range of about 18 to 40C, preferably at about 25 to 30-C, in particular at 28 to 30-C. The microorganism is cultivated under the stated conditions until the stationary phase is reached, for about 60 to 120 hours, preferably 70 to 75 hours.

The cultivation is advantageously carried out in ~everal stages, i.e. initially one or more precultures are prepared in a liguid nutrient medium and are then transferred into the actual production medium, the main eulture, for example in the ratio 1 s 10 by volume. The preculture is obtained, for example, by transferring a ~porulated mycelium into a nutrient solution and allowing it to grow for about 48 to 72 hours. The sporulated mycelium can be obtained by allowing the strain to grow for ~bout 7 days on a solid or liguid nutrient medium, for example yeast/malt agar.

The progre~s of the fermentation can be monitored by means of the pH of the culture or of the mycelium volume, by thin-layer chromatography or testing the biological ~ctivity.

The angucyclinones of the general formula I are present in the culture broth. Hence it is expedient for , '..;''~ '' ':,'~'. ..", 200~30 - 4 - :
the isolation of the substance to ~eparate the mycelium from the culture broth, for example by filtration or centrifugation. The compound of the formula I can then be isolated from the supernatant, expediently in the pH
range 2 to 8, preferably at pH values from 5 to 7. The substance can be extracted with conventional agents, for example polar solvents, for example lower alkanols. ~ ~
However, it is advantageous to pass the liquid over an ~ ;
adsorber resin such as, for example, those based on poly-styrene. The elution can then be carried out with a polar solvent, preferably lower alkanols such as, for example, methanol, which are possibly also mixed with water. The solvent can be removed from the eluate by distillation, and the agueous residue containing the angucyclinones can -~
be dried. ~ - ;

The compounds b and c of the formula I can be obtained not only microbiologically but also chemically -~
from the compound Ia. For this, the compound Ia is dissolved in solvents such as chloroform, methylene chloride, tetrahydrofuran, ethyl acetate or (C1 to C~
alcohols and ~tirred in the air with or without addition of air, with exclusion of light, for 1 to 20 days. The -duration of this reaction depends on the amount of air in -the reactlon mixture. The compound Ib is obtained a8 final product. It is possible in a subseguent reaction to prepare the compound of the formula Ic by irradiation j with W light (366 nm) of the resulting reaction solution ''"~'~ "~'' ~ r~
in a guartz flask for a period of 12 to 48 hours. ~ f~, The angucyclinones of the general formula I are colorless amorphous solids which are readily soluble in methanol, acetone, DNS0, dioxane and chloroform but insoluble in water and alkanes. The compounds of the general formula I can be incorporated in pharm~ceutical formulations appropriate for their stability. The `~
antibacterial and antiviral action and the action against ;
protozoa can be demonstrated in the agar diffusion test or by cell culture tests in vitro. The compounds shcw a .;

200430~

particularly good action in particular against Staphylococcu~ aureus and Staphylococcus pyogenes as well as against adenoviruses, HSVI and HSVII viruses as well as Trichomonas vaginalis ~protozoa). ~;~

~he invention i~ explained further in the examples which follow. As in the foregoing description, percentage data relate to weight.

E~amples:

1. a) Preparation of a suspension of spores of the producer strain 100 ml of nutrient solution (4 g of yeast `~
extract, 10 g of malt extract, 4 g of glucose, 1 1 of tapwater, pH before sterilization 7.3) in a 500 ml Erlenmeyer flask are inoculated with the strain DSN 4769 and incubated on a rotating shaker at 120 rpm and 27-C for 72 hours. Subse-quently 20 ml of culture liquid sre uniformly distributed in a 500 ml Erlenmeyer flask contain- ;~
ing the nutrient medium of the abovementioned compo~ition to which 20 g of agar/l have been ;added for solidification, and are decanted. The cultures are incubated at 27C for 10 to 14 days.
The spores which have resulted after this time in ~;;
a flask are rinsed out w~th 500 ml of deionized ~,,,r, water which contains one drop of a commercially available non-ionic surfactant (Triton X100, from Serva), and immediately used further or stored at -22-C. `~ -b) Preparation of a culture or preculture of the producer strain in an Erlenmeyer flask ~-A 500 ml Erlenmeyer flask containing 100 ml of a nutrient solution composed of 2 % meat meal, 10 %
malt extract, 1 % calcium carbonate and water ad ..... ...
: . . - .
:-,.
.... .

2()0~30 100 % (pH 7.2 before autocla~ing) is inoculated with a culture grown in a slant tube or with 0.2 ml of suspension of DSM 4769 gpores and i8 incubated on a shaker at 120 rpm and 27~C.
Maximum antibiotic production is reached after 72 hours. A 48-hour old submerged culture (5 %) from the same nutrient solution suffices to inoculate 10 and 100 1 fermenters. `~

2. Preparation of the angucyclinones A 10 1 fermenter inoculated with DSM 4769 is operated under the following conditions~

Nutrient medium: 30 g/l glycerol 2 g/l casein peptone ~-1 g/l R2HPO
1 g/l NaCl 0.5 g/l MgSO4 . 7H2O
5 ml/l trace element solution Trace elements: 3 g/l CaCl2 . 2H2O ,~
1 g/l FeC~O,H5 -0.2 g/l MnSO~ .. ,,,.,.~.. ,,,,!~, 0.1 g/l ZnCl2 0.025 g/l CuSO~ . 5H2O
0.02 g/l Na2B4O7 lOH2O
0.004 g/l CoCl 0.01 g/l Na2MoO4 2H2O , Incubation times 72 hours Incubation temperature: 30~C
Stirrer speeds 250 rpm Aerations 4 1 of air/min.
~' . -. ::
Foam production can be ~uppressed by repeated addition of a few drops of ethanolic polyol solution. The production maximum is reached after about 70 hours (pH = 5.3).

.;'~ " ' '' ... ..

- . . .
.. ~. . : .. .

3.a Isolation of the an~ucyclinones The fermenter contents of 8 1 are filtered and the filtrate is subsequently extracted with ;
3 x 6 1 of methylene chloride. The syrup (4 g) -remaining after concentration in a rotary evapor-ator is chromatographed on ~ilica gel (eluent ~ -CHCl3:MeOH 30:1). The result i~ the compound of the formula I ~ ;
a) with R1 -OH 330 mg R2 -OH ~ `
b) with Rl =0 220 mg RZ - OH ~--c) with R1 =0 220 mg -~
R2 =o b) Pre~aration of the compound of the formula I with Rl =0 and R2-OH
. ~: . :.... ,.,.-50 mg of the compound of the formula I with R1 -OH and R2 -OH are stirred in 10 ml of methylene chloride in the air with exclusion of iight for 24 days. The solvent iB evaporated in vacuo, and the residue i~ chromatographed on silica gel `",",' '," !,.j.,:.,."'."
(eluent CHCl3/MeOHs 30:1). 42 mg of the desired compound are obtained.
',,',' ':.~" `''',",''~':',', c) preparation of the compounds b and c of the formula Is ~ -100 mg of the compound of the formula Ia with R1 OH and R2 OH in CHCl3 (technical) in a quartz fla~k are irradiated with W light (366 nm) for ; ~;
24 hours. The residue after concentration in a ~ ~-rotary evaporator is chromatographed on silica gel (eluent CHCl3/MeOHs30/l). 7.3 mg of the ~ 5 compound Ib with Rl ~O and R2 -OH and 53 mg of the compound Ic with R1 =0 and R2 -O are obtained.

;:004304 -- 8 -- : :
Compound of the formula I

13C-NMR in CDCl3 / 1H-NMR 1n CDCl3 a b c R1 -OH R1 =o R1 =o C R2 -OH R2 -OH R2 =o ,~

1 65,7 196,7 5-4 ~-:: ::
2 44,1 53,8 2,2 - :.`-.
3 69,0 77,15 4 45,2 44,1 2,9 -.;-;
4A 136,4 146,4 135,7 133,6 7,5 . `
6 128,2 135,2 8,2 .
6A 137,2 135,0 .
7 63,3 181,1 .
7A 129,4 120,3 8 156,8 159,9 9 114,8 117,3 7,3 129,5 129,8 7,7 `~
11 120,2 119,5 7,9 11A 143,4 137,7 ~ `
12 187,5 lB4,3 12A 128,2 135,1 12B 140,0 134,3 13 29,1 29,7 1,5 14 56,0 56,4 4,05

Claims (11)

1. A compound of the formula I

in which a) R1 and R2 are hydroxyl, b) R1 is an oxo group and R2 is hydroxyl or c) R1 and R2 are an oxo group.
2. A process for the preparation of a compound of the formula I as claimed in 1, which comprises cultiva-tion of Streptomyces spec. DSM 4769 or the mutants and variants thereof until the said compound accumulates in the culture and isolation of this compound where appropriate.
3. The process as claimed in claim 2, wherein the microorganism is cultivated in a nutrient solution which contains 0.5 to 6 % qlycerol and 0.1 to 4 %
soybean meal, in each case based on the weight of the total nutrient solution.
4. The process as claimed in claim 3, wherein the nutrient solution contains 2 to 4 % glycerol and 0.5 to 2 % soybean meal.
5. The process as claimed in one or more of claims 2 to 4, wherein the cultivation is carried out in a temperature range of about 18 to 40°C.
6. The use of the compound of the formula I as claimed in claim 1 as a substance having therapeutic activity.
7. The use as claimed in claim 6, wherein the compound of the formula I is employed as antibiotic.
8. The use as claimed in claim 7, wherein the anti-biotic is employed against bacteria, viruses and protozoa.
9. Streptomyces spec. DSM 4769, its variants and mutants as long as they synthesize the compound of the formula I as claimed in claim 1.
10. A process for the preparation of the compounds Ib and c as claimed in claim 1, which comprises a) the compound Ia as claimed in claim 1 being dissolved in a solvent and incubated with exclusion of light, and the compound Ib being obtained and b) the reaction mixture obtained in a) being irradiated with UV light, and the compound Ic being obtained.
11. The compound as claimed in claim 1, and substantially as described herein.
CA002004304A 1988-12-01 1989-11-30 Angucyclinones from streptomycetes, a process for the preparation thereof and the use thereof Abandoned CA2004304A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3840519.9 1988-12-01
DE3840519A DE3840519A1 (en) 1988-12-01 1988-12-01 NEW ANGUCYCLINONE FROM STREPTOMYCETES, PROCESS FOR THEIR PREPARATION AND THEIR USE

Publications (1)

Publication Number Publication Date
CA2004304A1 true CA2004304A1 (en) 1990-06-01

Family

ID=6368254

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002004304A Abandoned CA2004304A1 (en) 1988-12-01 1989-11-30 Angucyclinones from streptomycetes, a process for the preparation thereof and the use thereof

Country Status (4)

Country Link
EP (1) EP0372383A1 (en)
JP (1) JPH02257887A (en)
CA (1) CA2004304A1 (en)
DE (1) DE3840519A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10105274A (en) * 1996-09-09 1998-04-24 Internatl Business Mach Corp <Ibm> Portable information processing equipment
US10696685B2 (en) 2015-06-03 2020-06-30 Universiteit Leiden Polyketides, methods of use and preparation
CN116730884B (en) * 2023-06-08 2024-02-13 长沙学院 Sulfur-containing angular cyclic dimer structure compound, preparation method and application thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721684A (en) * 1970-06-18 1973-03-20 Squibb & Sons Inc Rabelomycin

Also Published As

Publication number Publication date
DE3840519A1 (en) 1990-08-30
EP0372383A1 (en) 1990-06-13
JPH02257887A (en) 1990-10-18

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