NZ230352A - 2,3-dihydroxypropanoic (glyceric) acid derivatives and their preparation - Google Patents
2,3-dihydroxypropanoic (glyceric) acid derivatives and their preparationInfo
- Publication number
- NZ230352A NZ230352A NZ230352A NZ23035289A NZ230352A NZ 230352 A NZ230352 A NZ 230352A NZ 230352 A NZ230352 A NZ 230352A NZ 23035289 A NZ23035289 A NZ 23035289A NZ 230352 A NZ230352 A NZ 230352A
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- enzyme
- carried out
- alkyl group
- antibiotics
- Prior art date
Links
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- 239000002253 acid Substances 0.000 title description 5
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- DLRVVLDZNNYCBX-ZZFZYMBESA-N beta-melibiose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-ZZFZYMBESA-N 0.000 description 1
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- 239000006227 byproduct Substances 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
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- 239000011572 manganese Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
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- 230000001766 physiological effect Effects 0.000 description 1
- 229920001522 polyglycol ester Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 1
- NGFMICBWJRZIBI-UJPOAAIJSA-N salicin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1CO NGFMICBWJRZIBI-UJPOAAIJSA-N 0.000 description 1
- 229940120668 salicin Drugs 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000005918 transglycosylation reaction Methods 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/60—Unsaturated compounds containing ether groups, groups, groups, or groups the non-carboxylic part of the ether being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
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Abstract
It is possible with the aid of a Bacillus species or the appropriate enzymes obtained therefrom to degrade phosphoglycolipid antibiotics. The degradation products of the moenomycins have antibiotic activity or can be used as building block in the synthetic preparation of transglycosylase inhibitors.
Description
<div id="description" class="application article clearfix">
<p lang="en" class="printTableText">New Zealand Paient Spedficaiion for Paient Number £30352 <br><br>
o <br><br>
-r^' - • -rt« <br><br>
O <br><br>
ZZ0Z52 <br><br>
NO DRAWINGS <br><br>
Priority Date(s):. <br><br>
2^>- z- ■=&%■ <br><br>
Complete Specification Filed: <br><br>
Class: <br><br>
Publication Date: . IMJSL <br><br>
P.O. Journal, No: <br><br>
N.Z <br><br>
NEW ZEALAND <br><br>
Patents Act 1953 <br><br>
COMPLETE SPECIFICATION <br><br>
A new microorganism for breaking down moenomycins, a process for the breakdown, and the use of the breakdown products <br><br>
© <br><br>
He, HOECHST AKTIENGESELLSCHAPT, D-6230 Frankfurt am Main 80, Federal Republic of Germany, a corporation organized under the laws of the Federal Republic of Germany do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- <br><br>
- 1 - <br><br>
(Followed by 1A) <br><br>
23 0 3 521 <br><br>
nODOIIGT AKOIIDIiOBCDUiDOIIMUD Diiinn/ga HOD 00/r BSD <br><br>
Description <br><br>
A new microorganism for breaking down moenomycins, a process for the breakdown, and the use of the breakdown products <br><br>
Mbenomycin A (Fig. 1) is the main component of Flavomycin® which is used in livestock nutrition. Like other known phosphoglycolipid antibiotics it inhibits the biosynthesis of the peptidoglycan framework of the bacterial cell wall. Closer investigations showed that the transglycosylation reaction of the penicillin-binding protein lb of E. coli is inhibited by these substances [Huber 6., Antibiotics, V-l, pages 135 to 153 (1979)]. Attempts at specific enzymatic or microbial breakdown of phosphoglycolipid antibiotics have hitherto failed. <br><br>
Surprisingly, a new Bacillus species which is able to cleave the phosphoglycolipid antibiotics to defined end products has now been isolated from a contaminated fermenter for the preparation of flavomycin using Streptomyces ghanaensis. These end products have antibiotic activity or can be used as building blocks in the synthesis of new transglycosylase inhibitors. <br><br>
Hence the invention relates to: <br><br>
1. Bacillus spec. DSM 4675 and the variants and mutants thereof. <br><br>
2. The cleavage product of moenamycin A with the formula I <br><br>
23035? <br><br>
- 2 - <br><br>
UC <br><br>
3. The cleavage product: of the phosphoglycolipid antibiotics with the general formula <br><br>
R^-O-C^-CH-OR2 <br><br>
COOH (II) <br><br>
in which R1 is hydrogen or a phosphono group [-P0(0H)2] and R2 is a (C5 to C55)-alkyl group which can be branched or unbranched, saturated or unsaturated. <br><br>
4. The enzymes with whose aid the phosphoglycolipid antibiotics cem be cleaved at the phosphoglycosidic linkage, or the cleavage products specified under 3. can be cleaved at the monophosphate ester linkage. <br><br>
5. A process for the preparation of the breakdown products specified under 2. and 3., which comprises incubating phosphoglycolipid antibiotics with Bacillus spec. DSM 4675. <br><br>
6. The use of the substances specified under 2. and 3. as building block for the synthetic preparation of transglycosylase inhibitors or as substance having antibiotic activity. <br><br>
The invention will be described in detail hereinafter, especially in the preferred embodiments. It is furthermore defined in the claims. <br><br>
e . 230352 <br><br>
o <br><br>
- 3 - <br><br>
Bacillus spec, was deposited with the number DSH 4675 under the provisions of the Budapest Treaty at the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (German Microorganism and Cell Culture Collection) 5 in Braunschweig, FRG, on June 23, 1988. The characteristics of the strain may be said to be the following: <br><br>
1. Taxonomic properties of Bacillus sp. DSM 4675 ^ A) Morphology <br><br>
—/ - motile rods; up to 5 /m long; some in short <br><br>
10 chains <br><br>
- terminal spore; sporangium swollen <br><br>
- Gram-positive. <br><br>
B) Growth on various aedia (28"C; 48 hours) <br><br>
1. Antibiotic medlwm 3 (Difco) <br><br>
15 - rough, lobed colonies of diameter 1-2 mm <br><br>
2. Luria broth (Bacto tryptone 10 g/1; Bacto yeast 5 g/1; NaCl 5 g/1 <br><br>
- smooth, glossy round colonies of diameter 2-3 mm; opaque <br><br>
CD 20 3. Nutrient broth (Difco) <br><br>
- white, glossy colonies with irregular margin <br><br>
4. Christens en urea agar (Difco) _ - growth positive <br><br>
5. McConkey agar (Difco) <br><br>
25 - growth positive <br><br>
6. BRQIiAC agar (lactose) (Difco) <br><br>
- growth positive <br><br>
7. Simmons citrate agar (Difco) <br><br>
- growth negative <br><br>
23 0 3 <br><br>
- 4 - <br><br>
8. No growth in the presence of 7 or 10 % NaCl in a peptone/meat extract medium (Difco) <br><br>
C) Physiological properties <br><br>
1. Oxidase + <br><br>
2. Catalase + <br><br>
3. Hemolysis - <br><br>
4. Aminopeptidase <br><br>
5. Nitrate reduction - <br><br>
6. Phenylalanine deaminase - <br><br>
7. Growth at 30*C + <br><br>
40#C + <br><br>
50°C + <br><br>
8. Anaerobic growth <br><br>
- solid - <br><br>
- liquid - <br><br>
9. Gas formation from glucose - <br><br>
10. Indole formation <br><br>
11. Arginine dihydrase - <br><br>
12. Urea breakdown <br><br>
13. Esculin hydrolysis + <br><br>
14. Gelatin breakdown <br><br>
15. 0-Galactosidase 'tis. Lysine decarboxylase - <br><br>
17. Ornithine decarboxylase <br><br>
18. H2S production <br><br>
19. Tryptophan deaminase <br><br>
20. Alkal. phosphatase <br><br>
21. Voges-Proskauer reaction - <br><br>
D) Fermentation of carbohydrates C source Assimilation Acid formation <br><br>
Adipate Adonitol Arabinose Caprate Citrate <br><br>
230352 <br><br>
C source Assimilation Acid formation <br><br>
Dulcitol <br><br>
— <br><br>
Fructose <br><br>
+ <br><br>
+ <br><br>
Galactose <br><br>
— <br><br>
Gluconate <br><br>
+ <br><br>
Glucose <br><br>
+ <br><br>
+ <br><br>
Inositol <br><br>
— <br><br>
Lactose <br><br>
+ <br><br>
+ <br><br>
Malate <br><br>
- <br><br>
Malonate <br><br>
— <br><br>
Maltose <br><br>
+ <br><br>
+ <br><br>
Mannitol <br><br>
+ <br><br>
+ <br><br>
Mannose <br><br>
+ <br><br>
+ <br><br>
Melibiose <br><br>
+ <br><br>
+ <br><br>
Phenylacetate <br><br>
- <br><br>
Raffinose <br><br>
+ <br><br>
+ <br><br>
Rhamnose <br><br>
— <br><br>
Sucrose <br><br>
+ <br><br>
+ <br><br>
Salicin <br><br>
- <br><br>
Sorbitol <br><br>
— <br><br>
Trehalose <br><br>
+ <br><br>
+ <br><br>
Xylitol <br><br>
— <br><br>
- <br><br>
Xylose <br><br>
+ <br><br>
+ <br><br>
N-Acetyl-glucosamine <br><br>
— <br><br>
+ <br><br>
Taking account of taxonamic features and with the aid of "Bergey's Manual of Systematic Bacteriology" (Vol. 2, Williams and Wilkins publ., Baltimore, 1986) the strain can be assigned to the genus Bacillus. To determine the species, parallel comparative examinations of type cultures of Bacillus macerans, circulans, lentus, alcalo-philus , stearothermophilus , licheniformi s , polymyxa and fastidiosus were carried out. All the comparison strains showed distinct differences from Bacillus spec. DSM 4675. Nor were any of these strains able to break down phosphoglycolipid antibiotics, especially moenomycin A. The conclusion to be drawn from this is that the strain DSM <br><br>
- 6 - <br><br>
230 352 <br><br>
4675 is a new species. <br><br>
The invention also relates in each case to the mutants and variants which, as is known, may arise spontaneously or be generated by treatment with physical agents, for example irradiation, such as ultraviolet or X-rays, or with chemical mutagens such as, for example, ethyl me thane sulfonate (EMS), N-methyl-N' -nitro-N-nitrosoguani-dine (MNNG) or 2-hydroxy-4-methoxy-benzophenone (HOB). <br><br>
Suitable and preferred as carbon source for the aerobic fermentation of Bacillus spec. DSM 4675 are assimilable carbohydrates and sugar alcohols, such as glucose, lactose or mannitol, as well as carbohydrate-containing natural products such as malt extract. Suitable and preferred nitrogen-containing nutrients are: amino acids, peptides and proteins, as well as the breakdown products thereof, such as peptone or tryptone, furthermore meat extracts, milled seeds, for example of corn, beans, soybean or the cotton plant, disillation residues from the production of alcohol, meat meals or yeast extracts, as well as ammonium salts and nitrates. The nutrient solution may additionally contain, for example, chlorides , carbonates, sulfates or phosphates of the alkali metals or alkaline earth metals, iron, zinc and manganese as additional inorganic salts. <br><br>
The growth of the microorganism and the formation of the enzymes necessary for the breakdown reactions according to the invention is particularly good in a nutrient medium containing corn starch, soybean meal, sucrose, glycerol, peptone and/or com steep as carbon and nitrogen sources. <br><br>
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 or oxygen. The fermentation can take place in a temperature range from approximately room temperature to <br><br>
n i O <br><br>
o <br><br>
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230352 <br><br>
50 °C, preferably at about 35 to 37°C. The culturing time is generally 24 to 48 hours. <br><br>
The cultures of Bacillus DSM 4675 obtained in this way, or preparations thereof, can be used to cleave the 5 phosphoglycolipid antibiotics. These include, in particular, the antibiotics of the moenomycin group, for example pholipomycin15, the prasinomycins2), the diumycins (macar-bomycins)3) esanchoxnycin, prenomycin emd teichoxnycin, and other structurally related substances which have a 10 correspondingly functionalized phosphoglyceric acid [1) S. Takahashi et al.. Tetrahedron Lett. 1983. 499 <br><br>
2) F.L. Weisenborn et al.. Nature 213. 1092 (1967) <br><br>
3) S. Takahashi et al., J. Antibiot. 26. 542 (1973)]. <br><br>
The enzymes are particularly preferably used to break 15 down the moenomycins, for example Flavomycin. <br><br>
When Bacillus cells are used it is advantageous to permeabilize the latter, for example with cetyltrimethyl-ammonium salts. It is likewise possible to use protein isolates from the Bacillus cells, or enzyme extracts 20 which have been partially enriched, for example, by salting-out or chromatography or, of course, the purified enzyme. It is furthermore possible to employ the enzyme and cells in free or immobilized form. <br><br>
The enzymatic breakdown is depicted in the following 25 diagram using moenomycin A as an example. <br><br>
- 8 - <br><br>
230352 <br><br>
Enzymatic breakdown of moenomycin A <br><br>
O <br><br>
Moenomycin A <br><br>
Hoenotuyc inase <br><br>
MA <br><br>
» 23 0 3 52 <br><br>
It is evident from this diagram that two enzymes are needed to prepare the cleavage products. An enzyme, which the inventors have called moenomycinase, is required to cleave the phosphoglycosidic linkage. MOenomycinase is 5 associated with the cytoplasmic membrane of Bacillus spec. DSM 4675 and can be obtained from the microorganism by enzyme isolation methods known per se. <br><br>
Moenomycinase has a pH optimum of about 8.0-8.5, in particular 8.2-8.3. The temperature optimum of the enzyme 10 is 45—55°C, in particular 49-51 °C. Moenomyc inase has a K„ <br><br>
value for moenomycin A of 4-10 millimolar. <br><br>
Two cleavage products are obtained. Cleavage product I comprises the sugar component of the phosphoglycolipid antibiotics. Also obtained is the cleavage product with 15 the general formula II <br><br>
R^-O-CHo-CH-OR2 <br><br>
2 I II <br><br>
COOH <br><br>
in which r1 is a phosphono group and R2 is a (C5 to C55)-alkyl group, preferably a (C10 to C30) -alkyl group, in particular a (C20 to C^)-alkyl, each of which can be 20 branched or unbranched, saturated or unsaturated, preferably branched and unsaturated. <br><br>
Moenomyc ins are preferably employed as substrates, so that the resulting cleavage products are the substances corresponding to the compound ISC, as well as the com-25 pounds MB and MA (see formula diagram). <br><br>
Another enzyme is required for the dephosphorylation of the phosphoglyceric acid lipid, which is obtained by incubation with moenomycinase, of the general formula II in which R1 is hydrogen, and can also be obtained from 30 the microorganism according to the invention. The inventors have called this enzyme MBase. MBase can likewise be isolated from the microorganism by methods known per se. For example, the cells are disrupted with ultrasound, and <br><br>
o <br><br>
23 0 3! <br><br>
- 10 - <br><br>
the resulting crude extract is further enriched either by ammonium sulfate fractionation (25-55 % saturation) or ultracentrifugation. This is followed by dialysis. The moenomyc inase and MBase are finally separated by chroma-5 tography. <br><br>
The MBase is increasingly inactivated at temperatures above 37°C as well as when the pH falls in the acid pH range below pH 5. <br><br>
The cleavage of the moenomyc ins, as well as of the 10 phosphoglycolipid antibiotics can, as already mentioned, be carried out with whole cells or enzyme isolates. <br><br>
The reaction is generally carried out in aqueous medium at a pH of about 5.5-8.5, preferably pH 7-8. The reaction time is generally 5-48 hours, preferably about 24 hours. <br><br>
15 The reaction temperature can be from 4 to 60°C, preferably 30 to 37 °C. The substrate concentration ought to be in the range from 0.1 to 5 %, preferably 1 to 2 %. <br><br>
It is still possible to carry out the reaction at temperatures or pH values which are higher or lower than 20 stated. However, the moenomyc inase is then less active. <br><br>
The reaction products resulting from moenomycin A are the substances MB and MC depicted in the diagram. The product MA can be obtained by incubation of MB with MBase at 30 to 37*C, preferably at 35 to 37 *C, and pH 5.5 to 8.5, 25 preferably pH 6 to 8, over a period of about 24 hours. <br><br>
The said reaction products can be used as antibiotic (for example MB) or as building block for the synthesis of transglycosylase inhibitors (for example MA and MC). <br><br>
30 <br><br>
The invention is described in more detail by means of examples. Unless stated otherwise, percentage data relate to weight. <br><br>
a o <br><br>
o <br><br>
230352 <br><br>
- 11 - <br><br>
Example 1 <br><br>
Maintenance of the Bacillus spec. DSM 4675 strain <br><br>
Bacillus spec. DSM 4675 is maintained on the following solid nutrient medium (medium 1): <br><br>
5 Bacto tryptone (Difco) 10 g/1 Teast extract (Difco) 5 g/1 NaCl 5 g/1 <br><br>
Agar 15 g/1 <br><br>
pH 7.2 <br><br>
10 The medium is distributed over test tubes and sterilized at 121 °C for 30 minutes, then cooled, inoculated with the culture and incubated at 37°C for 2-3 days. <br><br>
The grown culture is rinsed off to provide the inoculum for the following, moenomyc in-containing main culture 15 (medium 2): <br><br>
O <br><br>
20 <br><br>
O <br><br>
25 <br><br>
Corn starch <br><br>
40 <br><br>
g/1 <br><br>
Soybean meal <br><br>
35 <br><br>
g/1 <br><br>
Sucrose <br><br>
10 <br><br>
g/1 <br><br>
CaCOa <br><br>
8 <br><br>
g/1 <br><br>
Corn steep <br><br>
4 <br><br>
g/i <br><br>
CoS04 <br><br>
20 <br><br>
mg/1 <br><br>
®Genapol (alkyl polyglycol ester <br><br>
5 <br><br>
ml/1 <br><br>
Moenomycin A <br><br>
3 <br><br>
g/1 <br><br>
pH 7.6 <br><br>
filtered) <br><br>
300 ml Erlenmeyer flasks each containing 30 ml of this medium are inoculated and then incubated at 37 °C and 190 rpm for 8-48 hours. Analysis of the culture filtrate by thin-layer chromatography shows that the compounds MA, 30 MB and MC are detectable as cleavage products of moenomycin, and that towards the end of the reaction there has been complete disappearance of the moenomycin employed. <br><br>
230352 <br><br>
- 12 - <br><br>
Example 2 <br><br>
Preparation of cell-free extracts <br><br>
To prepare cell-free extracts. Bacillus spec. DSM 4675 is cultured in a fermenter. For this, cells are rinsed off the agar plate to provide a 10 ml inoculum for a preculture (500 ml of medium 2 without Flavomycin in a 2 1 Erlenmeyer flask) which is then incubated at 37 °C and 190 rpm for 24 hours. <br><br>
A 12 1 laboratory fermenter containing 9 1 of medium 3 is used for the main culture stage: <br><br>
Peptone 12.5 g/1 <br><br>
Glycerol 20.0 tg/1 <br><br>
Citrate 2.0 g/1 <br><br>
KaHPO^ 1.5 g/1 <br><br>
MgS04 x 7H2O 0.5 g/1 <br><br>
FeCl3 x 6H20 0.04 g/1 <br><br>
Desmophen (propylene glycol) 5.0 ml/1 pH 6.8 <br><br>
This is inoculated with 500 ml of preculture and incubated at 37*C, 300 rpm and an aeration rate of 0.5 wm for 24 hours. <br><br>
The grown culture is centrifuged, and the cell paste is resuspended in potassium phosphate buffer (pH 7.0) 50 mM (1 g of wet cells + 2 ml of buffer). The cells are then disrupted with ultrasound, a French Press9 or Dyno Mill9, and the resulting crude extract is used for the conversion. <br><br>
In a test mixture containing 100 pi of crude extract, 12 mg of moenymycin and 900 pi of potassium phosphate buffer (pH 8.0) 50 mM there is within 7-24 hours at 37"C 50 % breakdown of the substrate employed. The reaction products found are MA, MB and MC. <br><br>
230352 <br><br>
Example 3 <br><br>
Preparative conversion of moenomycin A <br><br>
Preparative conversions are carried out in a 12 1 fermenter containing 8.2 1 of potassium phosphate buffer (pH 8.0) 50 mM, 800 ml of crude enzyme extract and 100 g of moenomycin A at 37 °C and 100 rpm. The progress of the conversion is followed by TLC. The entire reaction mixture is freeze-dried after 8-48 hours. The moenomycin breakdown is generally 40-60 % (UV analysis from the TLC). The resulting reaction products are MA, MB and MC. <br><br>
Example 4 <br><br>
Preparation of the breakdown products <br><br>
100 g of freeze-dried mixture from the enzymatic conversion were taken up in 2 1 of water and extracted twice with 2 1 of ethyl acetate each time. Centrifugation was necessary for complete phase separation in this case. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. 0.4 g (0.4 %) of a dark brown oil was obtained, and thin-layer chromatography in the system n-butanol/acetic acid/water = 3/1/2 on silica gel (Merck 60 F254 aluminum TLC sheets), spraying with molybdatophosphoric acid/cerium (IV) sulfate color reagent (abbreviated to PMS reagent hereinafter), showed that it comprised mainly component MA (Rf value = 0.85). <br><br>
The remaining aqueous phase was then extracted twice with 2 1 of n-butanol each time. Once again, centrifugation was necessary for phase separation. The combined butanol phases were then concentrated as far as possible, and the residue was taken up in a little water and finally freeze-dried. 7.4 g (7.4 %) of a yellow powder were obtained and were found on examination by thin-layer chromatography (using the abovementioned conditions and <br><br>
230352 <br><br>
the same detection) to comprise mainly the component MB (Rf = 0.52). <br><br>
The aqueous phase from which non-polar substances had been removed in this way was freeze-dried. The amount of residue resulting from this was 76.9 g (76.9 % with a total amount of 85 %). Thin-layer chromatography showed that this pale yellow powder was composed of a polar main substance, called MC (Rf = 0.1), remaining moenomycin A and by-products. <br><br>
The crude products of components MA, MB and MC obtained in this way were further purified as follows. <br><br>
Example 5 <br><br>
a) Purification of the breakdown product MA <br><br>
400 mg of MA. crude product were chramatographed on 120 g of silica gel (Merck 60, 15 - 40 mem) which had been adjusted to a pH of 7.5. (The column material had been pre treated in the following way for this purpose: the silica gel was stirred in 500 ml of 2N HC1 for one hour, then filtered off with suction and washed to neutrality. The pH was then adjusted to 7.5 with IN NaOH, and finally washing with 2 1 of water and 500 ml of methanol was carried out. The material pretreated in this way was dried and activated at 120°C overnight.) Chloroform/eth-anol = 1/1 was used as eluent. The substance was loaded onto the column in 3 ml of solvent mixture, and 216 fractions each of 2.5 ml were collected. Using TLC analysis (TLC plates and detection as in Example 1, solvent system as for column eluent), fractions 115-175 were combined, dried on sodium sulfate and finally evaporated to dryness. 27 mg of spectroscopically pure MA were obtained. <br><br>
23 0 352 <br><br>
b) Purification of -the breakdown product MB <br><br>
3.1 g of MB-containing crude product from the extraction were chromatographed on 500 g of silica gel which had been adjusted to a pH of 7.5 using the process explained in Example 2. Using a medium-pressure chromatography system (MPLC), chloroform/ethanol/water = 4/7/1.5 was used for the elution at a flow rate of 10 ml/min and a pressure of 2-5 bar. After a fore-run of 600 ml, 220 fractions each of 10 ml were collected, combining on the basis of the TLC. Besides mixed fractions containing MB, fractions 90-170 yielded 1.28 g of pure MB after evaporation, taking up in water and freeze-drying. <br><br>
c) Purification of the breakdown product MC <br><br>
2.2 g of polar crude product from the aqueous phase of the extraction were likewise chromatographed under pressure (MPLC). 500 g of silica gel with a pH of 7.5 were employed (process in Example 2), and the eluent used was ethyl acetate/i-propanol/water = 4/5/5. The amount to be loaded was suspended in methanol with 15 g of silica gel, the solvent was evaporated off, and the support treated in this way was introduced into a precolumn, and then elution was carried out at a flow rate of 5 ml/min under a pressure of 2-4 bar. A fore-run of 940 ml was followed by fractionation in 250 fractions each of 10 ml. The fractions were tested by thin-layer chromatography in the system ethyl acetate/i-propanol/water = 1/1/1 using PMS color reagent and detection of the UV absorption at 254 nm, and were combined. Besides mixed fractions, concentration of fractions 120-190 to the aqueous phase and subsequent freeze-drying revealed 1.3 g of pure MC, which was investigated by spectroscopy. <br><br>
Example 6 <br><br>
Blncidatxon of the structures of the products MA and MB obtained fm »oenonycin A by enzymatic breakdown. <br><br>
23 0 352 <br><br>
- 16 - <br><br>
(The numbers of the structures relate to the formula diagram on page 19) <br><br>
The structure deduced for MA was la. The assignment of the structure is based on the UC NMR spectrum of la. Reaction of la with diazomethane yielded the methyl ester lb which is characterized by a *H NMR and an EI mass spectrum. <br><br>
The structure deduced for MB on the basis of 13C and FAB mass spectrum was 2. Hydrogenation of 2 yielded the decahydro derivative 3a which reacted with diazomethane to give 3b, which had already been obtained previously from moenomycin A by another route. It is consistent with the proposed structures that it was possible to convert 2 (MB) enzymatically into la (MA). <br><br>
Description of the experiments las <br><br>
"c NMR (100.6 MHz, CD3OD): moenocinol moiety: 6 = 67.5 (C-l), 123.5 (C-2), 141.6 and 141.8 (C-3 and C-7), 32.3 and 32.5 (C-4 and C-5), 126.7 (c-6), 35.9 (C-8), 40.9 (C-9), 30.7 (C-10), 151.1 (C-ll), 33.4 (C-12), 122.7 (C-13), 137.3 (C-14), 36.4 (C-15), 27.7 (C-16), 125.3 (C-17), 132.2 (C-18), 25.9 (C-19), 17.8 (C-20), 16.1 (C-21), 109.2 (C-22), 27.3 (C-23 and C-24), 23.8 (C-25). <br><br>
Glyceric acid moiety: 6 = 175.9 (C-l), 80.6 (C-2), 64.1 (C-3). <br><br>
CzaH^O, (446.6) <br><br>
lb: <br><br>
la was converted into the H* form in aqueous solution using *Dowex 50 (H* form), la (H* form, 18.5 mg, 0.04 xomol) was dissolved in methanol (3 ml) and, at 0*C, excess ethereal diazomethane solution was added. The reaction mixture was maintained at 0aC for 2 h and at 20°C for 12 h and then evaporated to dryness. Column chromatography (5 g of Si02, petroleum ether/ethyl acetate 2:1) yielded lb (3 mg). <br><br>
230352 <br><br>
lH NMR (80 MHz, CDC13): 5 = 0.96 (s, 6H, CHa-23 and CH3-24), 1.61 (s, 6H), 1.68 (s, 3H), 1.73 (s, 3H) (4xCH3), 1.90-2.12 (allyl Hs), 2.62 (broad d, J = 7Hz, CH2-12), 3.78 (s, OCH3), 3.60-4.30 (CX^ and OCH signals), 4.62 (broad s, CH2-22), 4.87-5.47 (olefinic Hs). - C^H^O* (460.7), MS: m/z (%) = 460 (0.03), 271 (10), 230 (19), 199 (68), 43 (100). <br><br>
2; <br><br>
UC NMR (100.6 MHz, D20): moenocinol moiety: s - 68.6 (C-1), 124.5 (C-2), 142.9 (C-3), 34.6 (C-4), 34.0 (C-5, C-10), 128.1 (C-6), 143.6 (C-7), 37.8 (C-8), 44.1 (C-9), 151.4 (C-ll), 37.2 (C-12), 123.5 (C-13), 138.3 (C-14), 42.2 (C-15), 29.1 (C-16), 126.9 (C-17), 133.1 (C-18), 28.0 (C-19), 19.9 (C-20), 18.2 (C-21), 111.2 (C-22), 29.7 (C-23, 24), 25.9 (C-25). Glyceric acid moiety: S = 179.0 (C-l), 81.8 (C-2), 68.6 (C-3). - (526.7), FAB-MS <br><br>
(matrix: DMSO/glycerol): m/z = 615 (M-3H+4Na)+, 593 (M-2H+3Na)+, 571 (M-H+2Na)+, 492, 267, 231, 185, 165, 143, <br><br>
115. <br><br>
2 (14.9 mg, 28.3 pmol) and Pt02 (4 mg) were stirred in methanol (3 ml) and acetic acid (50 /tl) in an ^ atmosphere under normal conditions for 3 days. The catalyst was filtered off, and evaporation yielded 3a (13.5 mg). - CssHstOjP (536.7), FAB-MS (matrix: DMSO/glycerol: m/z = 625 (M-3H+4Na)+, 603 (M-2H+3Na)+, 581 (M-H+2Na)+, 558 (M-H+Na)\ 514, 500, 498, 432, 404, 362, 340, 298, 288, 266, 186, 164, 142, 115, 93. <br><br>
3a was treated in aqueous solution with the ion exchanger (Dowex 50, ft form) in order to liberate all acidic groups. The resin was filtered off and then the solution was freeze-dried. 8.5 mg (15.9 jimol) of the sample treated in this way were dissolved in methanol (2 ml). An excess of ethereal diazomethane solution was added at 0*C. The mixture was left to stand at 0aC for 2 h and at <br><br>
- 18 - <br><br>
230352 <br><br>
20°C for 12 h. Evaporation and column chromatography (5 g of Si02, petroleum ether/ethyl acetate 1:1) yielded 3b (4.0 mg). <br><br>
*H NMR (80 20 MHz, CDC13): S = 3.75 (s, OCH3 and 2 d, 3Jh p = 10 and 12 Hz, P(0CH3)2), 3.20 - 4.40 (OCHj, and OCH multiplets), - (578.8), MS: m/z (%) = 563 (0.1, <br><br>
M-CH3), 519 (1, H-COOCH3), 452 (1, M-(CH30)2P(0)0H), 381 (3, M-C14H29, breakage of the link between C-8 emd C-9 of the 25 perhydromoenocinol moiety), 229 (8, a), 212 (6, b), 127 (20), 57 (100). <br><br>
o <br><br>
- 19 - <br><br>
23 0 352 <br><br>
Q <br><br>
M_ <br><br>
^■^Joenoroycin A <br><br>
enzyme <br><br>
2 <br><br>
R <br><br>
a b <br><br>
H > ch3' <br><br>
enzyme <br><br>
HOOC r hct'^o <br><br>
H2/Pt <br><br>
ROOC <br><br>
o <br><br>
3 <br><br>
R <br><br>
a <br><br>
H "> <br><br>
b <br><br>
CH3' <br><br>
HjCO^VOH <br><br>
H-i-OH <br><br>
tHjOPlOUOCH^, <br><br>
»c ^CMjOPlOKOCHjjjJ <br><br>
VQv <br><br>
°> Njc^H^, <br><br></p>
</div>
Claims (1)
- <div id="claims" class="application article clearfix printTableText"> <p lang="en"> 250352<br><br> Example 7<br><br> Antibiotic activities of the cleavage products<br><br> An agar dilution test with Mueller-Hinton agar was carried out to determine the antibacterial activities (Antibiotics in Laboratory Medicine, V. Lorian, Ed., Baltimore 1986, pages 1-10).<br><br> Minimum inhibitory concentration (pg/ml)<br><br> Cleavage products Str. Staph. E.coli pyogenes aureus<br><br> 77 503 DC2<br><br> MA >100 >100 >100<br><br> MB 3.125 25 >100<br><br> MC >100 >100 >100<br><br> Example 8<br><br> Transglycosylase assay<br><br> The inhibition of the polymerization of the peptido-glycan-sugar chains by the cleavage products was carried out by the assay described by Izaki (J. Biol. Chem. 243. 3180-3192, 1968) using lipid intermediates from the cell membrane of E. coli K 12.<br><br> It emerges from this that moenomycin A (20 pg/ml) inhibits the transglycosylase reaction by 52.7 % and the cleavage product MB inhibits the enzyme by 32.9 %.<br><br> - 21 -<br><br> 2303o2<br><br> WHAT WE CLAIM IS:<br><br> 1. The compound of the formula II<br><br> R^-O-CHo-CH-OR2<br><br> 2-v-n-u* H;COOH;In which R1 Is hydrogen or a phosphono group and R2 Is a branched or unbranched, saturated or unsaturated (Cj to C2S)-alkyl group.;2. The compound as claimed in claim 1, wherein the alkyl group has a chain length of 10 to 30 carbon atoms.;3. The compound as claimed in claim 1 or 2, wherein the alkyl group has a chain length of 20 to 25 caxbon atoms.;4. A process for the preparation of the compound of the formula II as claimed in claim 1, which comprises incubating phosphoglycolipid antibiotics with Bacillus spec. DSM 4675 or an enzyme isolate obtained therefrom.;5. The process as claimed in claim 4, wherein incubation is carried out at a pH of 5.5 to 8.5.;6. A compound according to claim 1 substantially as herein described or exemplified.;7. a process according to 4 substantially as herein described or exemplified.;HOECHST Al ELLSCHAFT;By Their;HENRY \ GOES LTD By:;4 -18 JUH1991*<br><br> L<br><br> </p> </div>
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3828337 | 1988-08-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ230352A true NZ230352A (en) | 1991-07-26 |
Family
ID=6361268
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ230352A NZ230352A (en) | 1988-08-20 | 1989-08-18 | 2,3-dihydroxypropanoic (glyceric) acid derivatives and their preparation |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0355679B1 (en) |
JP (2) | JP2863557B2 (en) |
KR (1) | KR900003361A (en) |
AT (1) | ATE134641T1 (en) |
AU (2) | AU619034B2 (en) |
DE (1) | DE58909610D1 (en) |
DK (1) | DK407789A (en) |
ES (1) | ES2085855T3 (en) |
FI (1) | FI893878A (en) |
GR (1) | GR3019332T3 (en) |
IL (1) | IL91354A0 (en) |
NO (1) | NO893327L (en) |
NZ (1) | NZ230352A (en) |
PH (1) | PH26511A (en) |
PT (1) | PT91469B (en) |
ZA (1) | ZA896310B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2085855T3 (en) * | 1988-08-20 | 1996-06-16 | Hoechst Ag | NEW MICROORGANISM FOR THE DEGRADATION OF MOENOMYCINES, PROCEDURE FOR DEGRADATION, AS WELL AS THE USE OF DEGRADATION PRODUCTS. |
DE59208669D1 (en) * | 1991-03-08 | 1997-08-14 | Hoechst Ag | Process for producing MA |
US5316929A (en) * | 1991-03-08 | 1994-05-31 | Hoechst Aktiengesellschaft | Process for the preparation of MA |
EP0652205A3 (en) * | 1993-11-04 | 1995-08-30 | Hoechst Ag | Moenomycin degradation products containing hydroxylated or oxidized lateral lipid chain and moenomycin analogs, process for preparing and their use. |
DE19709897A1 (en) * | 1997-03-11 | 1998-09-17 | Hoechst Ag | Bismuth salts of antibiotics of the moenomycin group, process for their preparation, their use and medicaments containing such salts |
EP0872556A3 (en) * | 1997-04-17 | 2000-06-14 | Hoechst Aktiengesellschaft | Process for the preparation of moenomycin A |
EP1069130B1 (en) * | 1999-07-15 | 2004-08-11 | Hoechst Marion Roussel | Moenomycin A Derivatives, their preparation, and use as antibacterial products |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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NL6601300A (en) * | 1966-02-01 | 1967-08-02 | Stamicarbon | |
EP0130327B1 (en) * | 1983-05-21 | 1987-11-04 | Hoechst Aktiengesellschaft | Moenomycin-a derivatives, their preparation and their use as antibiotics |
ES2085855T3 (en) * | 1988-08-20 | 1996-06-16 | Hoechst Ag | NEW MICROORGANISM FOR THE DEGRADATION OF MOENOMYCINES, PROCEDURE FOR DEGRADATION, AS WELL AS THE USE OF DEGRADATION PRODUCTS. |
-
1989
- 1989-08-16 ES ES89115069T patent/ES2085855T3/en not_active Expired - Lifetime
- 1989-08-16 AT AT89115069T patent/ATE134641T1/en not_active IP Right Cessation
- 1989-08-16 EP EP89115069A patent/EP0355679B1/en not_active Expired - Lifetime
- 1989-08-16 DE DE58909610T patent/DE58909610D1/en not_active Expired - Fee Related
- 1989-08-17 FI FI893878A patent/FI893878A/en not_active Application Discontinuation
- 1989-08-17 PT PT91469A patent/PT91469B/en not_active IP Right Cessation
- 1989-08-18 PH PH39114A patent/PH26511A/en unknown
- 1989-08-18 IL IL91354A patent/IL91354A0/en unknown
- 1989-08-18 AU AU39985/89A patent/AU619034B2/en not_active Ceased
- 1989-08-18 JP JP1211531A patent/JP2863557B2/en not_active Expired - Lifetime
- 1989-08-18 DK DK407789A patent/DK407789A/en not_active Application Discontinuation
- 1989-08-18 KR KR1019890011754A patent/KR900003361A/en not_active Application Discontinuation
- 1989-08-18 NZ NZ230352A patent/NZ230352A/en unknown
- 1989-08-18 ZA ZA896310A patent/ZA896310B/en unknown
- 1989-08-18 NO NO89893327A patent/NO893327L/en unknown
-
1991
- 1991-12-02 AU AU88353/91A patent/AU635452B2/en not_active Ceased
-
1996
- 1996-03-15 GR GR960400720T patent/GR3019332T3/en unknown
-
1998
- 1998-05-18 JP JP10135487A patent/JPH1171323A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
DK407789A (en) | 1990-02-21 |
GR3019332T3 (en) | 1996-06-30 |
NO893327L (en) | 1990-02-21 |
AU8835391A (en) | 1992-02-06 |
JPH1171323A (en) | 1999-03-16 |
NO893327D0 (en) | 1989-08-18 |
EP0355679A2 (en) | 1990-02-28 |
AU3998589A (en) | 1990-02-22 |
PT91469B (en) | 1995-05-04 |
PT91469A (en) | 1990-03-08 |
EP0355679A3 (en) | 1991-07-24 |
KR900003361A (en) | 1990-03-26 |
AU619034B2 (en) | 1992-01-16 |
DK407789D0 (en) | 1989-08-18 |
IL91354A0 (en) | 1990-03-19 |
ZA896310B (en) | 1990-04-25 |
JPH02150273A (en) | 1990-06-08 |
FI893878A (en) | 1990-02-21 |
PH26511A (en) | 1992-08-07 |
ATE134641T1 (en) | 1996-03-15 |
FI893878A0 (en) | 1989-08-17 |
DE58909610D1 (en) | 1996-04-04 |
EP0355679B1 (en) | 1996-02-28 |
JP2863557B2 (en) | 1999-03-03 |
AU635452B2 (en) | 1993-03-18 |
ES2085855T3 (en) | 1996-06-16 |
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