WO1993013094A1 - Archazolides, leur procede de fabrication et agents les renfermant - Google Patents

Archazolides, leur procede de fabrication et agents les renfermant Download PDF

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Publication number
WO1993013094A1
WO1993013094A1 PCT/EP1992/002980 EP9202980W WO9313094A1 WO 1993013094 A1 WO1993013094 A1 WO 1993013094A1 EP 9202980 W EP9202980 W EP 9202980W WO 9313094 A1 WO9313094 A1 WO 9313094A1
Authority
WO
WIPO (PCT)
Prior art keywords
archazolide
methanol
archazolides
nych
nhch
Prior art date
Application number
PCT/EP1992/002980
Other languages
German (de)
English (en)
Inventor
Gerhard Höfle
Hans Reichenbach
Florenz Sasse
Heinrich Steinmetz
Original Assignee
GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF)
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 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) filed Critical GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF)
Publication of WO1993013094A1 publication Critical patent/WO1993013094A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings

Definitions

  • the invention relates to archazolides of the following general formula:
  • NYCH 3 is NHCH 3 or
  • NYCH 3 is N (CH 3 ) 2
  • the invention relates to an archazolid of the empirical formula C 42 H 62 N 2 SO 7 with the following parameters:
  • the invention relates to archazolides which can be prepared by isomerizing the above-described archazolide by UV radiation and, if appropriate, separating the isomer mixture by chromatography in a manner known per se.
  • the invention relates to a process for the preparation of the archazolide of the empirical formula C 42 H 62 N 2 SO 7 with the parameters specified above, this process being characterized in that
  • This method according to the invention can be characterized in that - adsorbed on Amberlite XAD16,
  • Variant (b) receives, or
  • the invention further relates to an agent that consists of one or more archazolides according to the invention or comprises these in addition to customary auxiliaries, for example carriers and diluents.
  • the bacterium Archangium gephyra belongs to the order of the
  • the Ar 3548 production strain was isolated in January 198 at the Deutschen für Biotechnologische Anlagen mbh (GBF) from a soil sample from the Karawanken in Austria. The strain was deposited on November 13, 1991 at the German Collection of Microorganisms (DSM) under number DSM 6806. The characteristics of the production strain are consistent with the description of Archangium gephyra in Bergey's Manual of Systematic
  • the stock culture is carried out on agar plates, preferably on yeast agar (VY / 2 agar).
  • This medium contains 0.5% baker's yeast, 0.1% CaCl 2 x 2 H 2 O, 0.1 ⁇ g / l vitamin B 12 and 1.2% agar.
  • the pH is adjusted to 7.4.
  • the plates are incubated at 30 ° C. A.3. Morphological description
  • the vegetative cells are long, slender rods with tapered ends, approximately 0.8 x 6 - 10 ⁇ m. Due to the
  • the myxospores are short, clumsy, very thick and well rounded rods, often somewhat irregular in outline, and always strongly refractive. They measure approximately 1.4-1.8 x 1.8-2.2 ⁇ m.
  • the Ar 3548 strain produces a substance, namely archazolide, that inhibits the growth of human cancer cell lines and other animal cell cultures and the growth of fungi.
  • the inhibitor can be isolated both from the cells and from the culture supernatant.
  • a typical fermentation proceeds as follows: A fermentor with 350 1 working volume is filled with 300 1 culture medium (composition: 0.5%
  • Adsorber resin (Amberlite XAD-16) added. Inoculation is carried out with 10 l of a 2-day-old preculture which was produced in the same medium in a correspondingly smaller fermenter. It is fermented at 30 ° C. with a stirring speed of 150 rpm and aeration of 10% by volume per min. Initial foam formation is prevented by adding 50 ml of silicone anti-foam (e.g. Tegosipon). The pH increases during the fermentation. The increase is limited to 7.8 by adding 5% sulfuric acid. The fermentation is ended after 6 days.
  • silicone anti-foam e.g. Tegosipon
  • Archazolid very effectively inhibits the growth of human cancer cell lines and other animal cell cultures without immediately killing the cells. Under the influence of archazolide, adherently growing cells round off and become freely mobile. Archazolid inhibits the growth of certain fungi (see table).
  • HeLa (ATCC CCL 2) 1ng / ml
  • the resin is sieved from a 100 l fermentation batch of the Ar 3548 strain in the presence of 1 l adsorber resin (Amberlite XAD 16) and eluted with 5 l methanol over a period of 2.5 hours.
  • the eluate is concentrated to the water phase and extracted 3 times with ethyl acetate in order to separate polar constituents.
  • the ethyl acetate extract is concentrated.
  • the remaining crude extract (12 g) is dissolved in 200 ml of methanol and fractionated in 2 portions over a Sephadex-LH20 column (62 mm x 63 mm) at a flow of 3.5 ml / min.
  • Eluent methanol Detection at 227 nm and by TLC chromatography.
  • the fractions containing archazolide (4.1 g) are in 10 0.41 g portions over a preparative Nucleosil C-18, 7 ⁇ m column (250 x 16 mm) with the mobile solvent methanol / water 85/15 and a flow of 15 ml / min (detection at 227 nm) chromatographed. After evaporation of the fractions containing Archazolid until

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des archazolides de formule générale (I) ainsi que leur procédé de fabrication et des agents renfermant des archazolides.
PCT/EP1992/002980 1991-12-24 1992-12-22 Archazolides, leur procede de fabrication et agents les renfermant WO1993013094A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4142951.6 1991-12-24
DE19914142951 DE4142951C1 (fr) 1991-12-24 1991-12-24

Publications (1)

Publication Number Publication Date
WO1993013094A1 true WO1993013094A1 (fr) 1993-07-08

Family

ID=6448119

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/002980 WO1993013094A1 (fr) 1991-12-24 1992-12-22 Archazolides, leur procede de fabrication et agents les renfermant

Country Status (3)

Country Link
AU (1) AU3257793A (fr)
DE (1) DE4142951C1 (fr)
WO (1) WO1993013094A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013375A1 (fr) * 1996-09-23 1998-04-02 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Composes a effet antimycotique et cytostatique, leur procede de production, agents contenant ces composes et dsm 11 092

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Keine einschl{gigen Dokumente gefunden *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013375A1 (fr) * 1996-09-23 1998-04-02 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Composes a effet antimycotique et cytostatique, leur procede de production, agents contenant ces composes et dsm 11 092
DE19638870B4 (de) * 1996-09-23 2009-05-14 Helmholtz-Zentrum für Infektionsforschung GmbH Tubulysine, Verfahren zu ihrer Gewinnung und sie enthaltende Mittel

Also Published As

Publication number Publication date
AU3257793A (en) 1993-07-28
DE4142951C1 (fr) 1993-05-13

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