DE2039061A1 - Partially amidated l-asparaginases - with chemotherapeutic action - Google Patents
Partially amidated l-asparaginases - with chemotherapeutic actionInfo
- Publication number
- DE2039061A1 DE2039061A1 DE19702039061 DE2039061A DE2039061A1 DE 2039061 A1 DE2039061 A1 DE 2039061A1 DE 19702039061 DE19702039061 DE 19702039061 DE 2039061 A DE2039061 A DE 2039061A DE 2039061 A1 DE2039061 A1 DE 2039061A1
- Authority
- DE
- Germany
- Prior art keywords
- asparaginases
- partially amidated
- asparaginase
- carbodiimide
- amino
- 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.)
- Pending
Links
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 title claims abstract description 23
- 108010024976 Asparaginase Proteins 0.000 title claims abstract description 23
- 230000000973 chemotherapeutic effect Effects 0.000 title abstract 2
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 9
- 150000001718 carbodiimides Chemical class 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 150000001408 amides Chemical class 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 5
- 229940126601 medicinal product Drugs 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 3
- 241000588724 Escherichia coli Species 0.000 abstract description 2
- 230000009435 amidation Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 150000002337 glycosamines Chemical class 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 241000607715 Serratia marcescens Species 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XNPOFXIBHOVFFH-UHFFFAOYSA-N N-cyclohexyl-N'-(2-(4-morpholinyl)ethyl)carbodiimide Chemical compound C1CCCCC1N=C=NCCN1CCOCC1 XNPOFXIBHOVFFH-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
- C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
- C12N9/82—Asparaginase (3.5.1.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
- C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
- C12Y305/01001—Asparaginase (3.5.1.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Partiell amidierte L-Asparaginasen Es ist bekannt, die Carboxylgruppen von Proteinen in Gegenwart eines wasserlöslichen Carbodiimids mit nucleophilen Substanzen umzusetzen. Hierbei entstehen die entaprechenden Amidderivate mit neuen physiko-chemischen Eigenschaften fj. Biol. Chem. 242 (1967) 24477. Partially amidated L-asparaginases It is known to have carboxyl groups of proteins in the presence of a water-soluble carbodiimide with nucleophilic substances to implement. This creates the corresponding amide derivatives with new physico-chemical ones Properties fj. Biol. Chem. 242 (1967) 24477.
Enzyme sind jedoch, soweit aus der Fachliteratur bekannt, bisher noch nicht unter Erhalt ihrer enzymatischen Aktivität derart modifiziert worden. Bei der hohen Spezifität und Instabilität der meisten Enzyme fUhren bereits leichte chemische Eingriffe zu einer irreversiblen Denaturierung und damit auch zu einem Verlust der enzymatischen Aktivität.However, so far as is known from the specialist literature, enzymes are still used has not been so modified while retaining their enzymatic activity. at The high specificity and instability of most enzymes lead to even slight reactions chemical interventions to an irreversible denaturation and thus also to a Loss of enzymatic activity.
Gegenstand der Erfindung sind nun partiell amidierte L-Asparaginasen. Diese werden erfindungsgemäß dadurch hergestellt, daß man B-Asparaginasen in Gegenwart eines Carbodiimids mit einer nucleophilen Komponente umsetzt.The invention now relates to partially amidated L-asparaginases. According to the invention, these are prepared by adding B-asparaginases in the presence a carbodiimide reacts with a nucleophilic component.
Gegenstand der Erfindung sind ferner Arzneimittel mit einem Gehalt an den genannten partiell amidierten L-Asparaginasen.The invention also relates to medicaments with a content on the partially amidated L-asparaginases mentioned.
L-Asparaginase (L-Aaparaginamidohydrolase, EC 3.5.1.1) hat kürslich Bedeutung als Chemotherapeutikum erlangt [Recent Results in Cancer Research, Vol. 33, 1970]. Die Applikation erfolgt in erater Linie durch intravenöse Injektion. Dabei verteilt sich das Enzym im extrazellulären Raum und wird nach einer gewissen Zeit abgebaut und ausgeschieden.L-asparaginase (L-aaparaginamidohydrolase, EC 3.5.1.1) has been purchased Gaining importance as a chemotherapeutic agent [Recent Results in Cancer Research, Vol. 33, 1970]. The application takes place in the erater line by intravenous injection. The enzyme is distributed in the extracellular space and becomes one degraded and eliminated for a certain period of time.
Die erfindungsgemäß hergestellten, neuen Derivate können teilweise kristallisiert werden und unterscheiden sich von den als Ausgangsprodukten dienenden L-Asparaginasen durch einen höheren isoelektrischen Punkt und somit durch eine geringere Wanderungsgeschwindigkeit zur Anode bzw. durch eine Wanderung zur Kathode. Die unterschiedlichen physiko-chemischen Eigenschaften dieser partiell amidierten L-Asparaginasen bewirken nun auch in vivo ein verändertes Verhalten, welches unter anderem durch eine veränderte Halbwertszeit zum Ausdruck kommt.The novel derivatives prepared according to the invention can in part are crystallized and differ from those used as starting products L-asparaginases by a higher isoelectric point and thus by a lower one Migration speed to the anode or due to a migration to the cathode. The different effect the physico-chemical properties of these partially amidated L-asparaginases now also in vivo a changed behavior, which among other things was changed by a Half-life is expressed.
Grundsätzlich sollen die neuen erfindungagemäßen Verbindungen als Arzneimittel für die gleichen Indikationen und in gleichen Dosierungen verwendet werden wie L-Asparaginase.In principle, the new compounds according to the invention as Medicines used for the same indications and in the same dosages become like L-asparaginase.
FUr das erfindungsgemäße Verfahren können nach beliebigen Methoden erhaltene L-Asparaginasen Verwendung finden, z.B.Any methods can be used for the process according to the invention L-asparaginases obtained can be used, e.g.
solche aus-den Mikroorganismen Escherichia coli oder Serratia sareeecan.those from the microorganisms Escherichia coli or Serratia sareeecan.
Zur Aktivierung der Carboxylgruppen der L-Asparaginasen kommen die in den betreffenden Lösungsmitteln löslichen Carbodiimide, wie z.B. 1-Äthyl-3-dimethylaminopropylcarbodiimid, 1-Cyclohexyl-3-(2-morpholinoäthyl)carbodiimid oder entsprechende Analoga, in Betracht.To activate the carboxyl groups of the L-asparaginases come the carbodiimides soluble in the solvents concerned, such as 1-ethyl-3-dimethylaminopropylcarbodiimide, 1-Cyclohexyl-3- (2-morpholinoethyl) carbodiimide or corresponding analogs, into consideration.
Als nucleophile Reaktionspartner eignen sich hauptsächlich die Amide oder Ester der Aminosäuren, jedoch können gane allgemein sämtliche Verbindungen mit nucleophilem Charakter eingesetzt werden, wobei hier z B. Aminozucker, Amine usw. genannt seien.The amides are mainly suitable as nucleophilic reactants or esters of amino acids, but generally all compounds can be used be used with nucleophilic character, here, for example, amino sugars, amines etc. may be mentioned.
Die Umsetzung erfolgt in v'äßriger Lösung, gegebenenfalls auch in mit Wasser mischbaren Lösungsmitteln, wie z.-B. Aceton, Alkohol, Dioxan usw. Der pH-Wert soll etwa zwischen 3 und 7 liegen.The reaction takes place in aqueous solution, if necessary also in water-miscible solvents such as Acetone, alcohol, dioxane, etc. The The pH should be between 3 and 7.
Als zweckmäßig hat es sich erwiesen, L-Asparaginase in einer Konzentration zwischen 0,1 und 5 ffi und die nucleophile Somponente in einer Konzentration zwischen 0,01 und 1 molar vorzulegen und die Reaktion mit dem Carbodiimid zu starten (Endkonzentration zwischen 0,01 und 0,1 molar). Durch Variation der Temperatur, der Zeit sowie der Konzentration der Reaktionspartner kann die Geschwindigkeit sowie der Grad der Umsetzung beeinflußt werden. Zweckmäßig ist ein Amidierungsgrad bis zu etwa 20 %. Die Reaktion kann durch Zusatz von organischen Säuren, wie z.B. Ameisensäure, Essigsäure usw.It has proven to be useful to use L-asparaginase in one concentration between 0.1 and 5 ffi and the nucleophilic component in a concentration between 0.01 and 1 molar and start the reaction with the carbodiimide (final concentration between 0.01 and 0.1 molar). By varying the temperature, the time and the Concentration of the reactants can affect the speed as well as the degree of implementation to be influenced. A degree of amidation of up to about 20% is expedient. The reaction can be achieved by adding organic acids such as formic acid, acetic acid, etc.
oder deren Salzen abgestoppt werden. Die anschließende Isolierung der bei der Reaktion entstandenen partiell amidierten L-Asparaginasen erfolgt nach den üblichen Methoden der Proteinchemie, also beispielsweise durch Ausfällen mit Polyäthylenglykol, organischen Lösungsmitteln oder Salzen, durch Adsorption an Hydroxylapatit oder Cellulosen oder aber auch durch Gefriertrocknung, gegebenenfalls nach vorhergehender. Entsalzung mittels Dialyse oder Gelchromatographie.or their salts are stopped. The subsequent isolation the partially amidated L-asparaginases formed in the reaction takes place after the usual methods of protein chemistry, for example by precipitating with Polyethylene glycol, organic solvents or salts, by adsorption on hydroxyapatite or celluloses or else by freeze-drying, if appropriate after the preceding. Desalination using dialysis or gel chromatography.
Die in den Beispielen aufgeführten partiell amidierten L-Asparaginasen wurden nach der folgenden allgemeinen Vorschrift gewonnen: L-Asparaginase (210 bis 240 E/mg) und die nucleophile Eomponente werden in der gewünschten Konzentration in Wasser gelöst und mit verdünnter HC1 oder NaOH auf einen bestimmten pH-Wert eingestellt. Die Reaktion wird durch Zugabe einer wäßrigen Carbodiimidlösung (Endkonzentration s. Tabelle) gestartet, gegebenenfalls wird der pH-Wert korrigiert. Nach einer bestimmten Zeit wird die Reaktion durch HinzufUgen des doppelten Volumens 1 M Natriumacetatlösung abgestoppt. Diese Mischung wird gegen Wasser dialysiert und dann der nichtdialysierbare Rückstand gefriergetrocknet. Die Ausbeuten sind nahe zu quantitativ.The partially amidated L-asparaginases listed in the examples were obtained according to the following general procedure: L-asparaginase (210 to 240 U / mg) and the nucleophilic Eomponente are in the desired concentration dissolved in water and adjusted to a certain pH value with dilute HCl or NaOH. The reaction is stopped by adding an aqueous carbodiimide solution (final concentration see table), the pH value is corrected if necessary. After a certain Time the reaction by adding twice the volume of 1 M sodium acetate solution stopped. This mixture is dialyzed against water and then the non-dialyzable Freeze-dried residue. The yields are almost too quantitative.
T a b e l l e
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702039061 DE2039061A1 (en) | 1970-08-06 | 1970-08-06 | Partially amidated l-asparaginases - with chemotherapeutic action |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702039061 DE2039061A1 (en) | 1970-08-06 | 1970-08-06 | Partially amidated l-asparaginases - with chemotherapeutic action |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2039061A1 true DE2039061A1 (en) | 1972-02-10 |
Family
ID=5779001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19702039061 Pending DE2039061A1 (en) | 1970-08-06 | 1970-08-06 | Partially amidated l-asparaginases - with chemotherapeutic action |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2039061A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998056410A1 (en) * | 1997-06-09 | 1998-12-17 | Childrens Hospital Los Angeles | Utilization of wolinella succinogenes asparaginase to treat diseases associated with asparagine dependence |
| US6991788B1 (en) | 1997-06-09 | 2006-01-31 | Childrens Hospital Los Angeles | Utilization of wolinella succinogenes asparaginase to treat diseases associated with asparagine dependence |
-
1970
- 1970-08-06 DE DE19702039061 patent/DE2039061A1/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998056410A1 (en) * | 1997-06-09 | 1998-12-17 | Childrens Hospital Los Angeles | Utilization of wolinella succinogenes asparaginase to treat diseases associated with asparagine dependence |
| US6991788B1 (en) | 1997-06-09 | 2006-01-31 | Childrens Hospital Los Angeles | Utilization of wolinella succinogenes asparaginase to treat diseases associated with asparagine dependence |
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