AZASERINE CAS 115-02-6
Introduction：Basic information about AZASERINE CAS 115-02-6, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
AZASERINE Basic information
| Product Name: | AZASERINE |
| Synonyms: | serine,diazoacetate(ester);O-DIAZOACETYL-L-SERINE;azaserin;azs;ci337;ci-337;cl337;cn-15,757 |
| CAS: | 115-02-6 |
| MF: | C5H7N3O4 |
| MW: | 173.13 |
| EINECS: | 204-061-6 |
| Product Categories: | Antibiotics |
| Mol File: | 115-02-6.mol |
AZASERINE Chemical Properties
| Melting point | 146-162° (dec) |
| alpha | D27.5 -0.5° (c = 8.46% in H2O at pH 5.18) |
| Boiling point | 303.75°C (rough estimate) |
| density | 1.5830 (rough estimate) |
| refractive index | 1.6190 (estimate) |
| storage temp. | 2-8°C |
| solubility | H2O: 50 mg/mL, clear, yellow |
| pka | 8.55(at 25℃) |
| form | lyophilized powder |
| color | Light-yellow needles from EtOH (aq) |
| Optical Rotation | -0.527.5 (H2O) |
| Merck | 13,902 |
| BRN | 1726602 |
| InChI | 1S/C5H7N3O4/c6-3(5(10)11)2-12-4(9)1-8-7/h1,3H,2,6H2,(H,10,11)/t3-/m0/s1 |
| InChIKey | MZZGOOYMKKIOOX-VKHMYHEASA-N |
| SMILES | N[C@@H](COC(=O)C=[N+]=[N-])C(O)=O |
| IARC | 2B (Vol. 10, Sup 7) 1987 |
| EPA Substance Registry System | Azaserine (115-02-6) |
Safety Information
| Hazard Codes | T |
| Risk Statements | 25-40 |
| Safety Statements | 53-36/37/39-45 |
| RIDADR | UN 3462 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | VT9625000 |
| F | 10 |
| HazardClass | 6.1(b) |
| PackingGroup | III |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Acute Tox. 3 Oral Carc. 2 |
| Hazardous Substances Data | 115-02-6(Hazardous Substances Data) |
| Toxicity | LD50 in mice, rats (mg/kg/day): 150, 170 orally (Sternberg, Philips) |
| Chemical Properties | Light-yellow needles from EtOH. |
| Originator | Azaserine,TG InternationalChemical Co. |
| Uses | antineoplastic, amino acid antagonist |
| Uses | Reagent used to induce pancreatic cancer in experimental animal models. |
| Definition | ChEBI: A carboxylic ester resulting from the formal condensation of the carboxy group of diazoacetic acid with the alcoholic hydroxy group of L-serine. An antibiotic produced by a Streptomyces species. |
| Manufacturing Process | The azaserine is produced by microbiological synthesis using culture ofStreptoniyces fragili: 10 gallons of a nutrient medium having the following composition (%):glucose1.0, soybean expeller oil meal 1.0, acid hydrolyzed casein 0.5, debitteredyeast 0.5, sodium chloride 0.5, water sufficient to make 100.0% is placed in a30 gallon stainless steel fermenter, the pH adjusted to 7.5 with 6 N sodiumhydroxide solution and 0.1% calcium carbonate added. The medium issterilized by heating at 121°C for 30 min after which the pH of the medium is6.85. The medium is cooled and inoculated with the spares from two fourteenday old Moyer's sporulation agar slant cultures of Streptoniyces fragilissuspended in 20 ml of sterile 0.01% castile soap solution. The culture mixtureis incubated at 27°C for 24 h during which time aeration is supplied through asparger at the rate of one volume of air per volume of medium per minute. The incubated culture thus obtained is used to inoculate the main culture asdescribed below. 150 gallons of a medium having the following composition(%): glucose 1.0, soybean expeller oil meal 1.0, acid hydrolyzed casein 0.5,debittered yeast 0.5, sodium chloride 0.5, ammonium nitrate 0.25, watersufficient to make 100.0 percent. 6 N sodium hydroxide solution-sufficient tobring the pH to 7.5,calcium carbonate - (added after pH adjustment) is placedin a 200-gallon stainless steel fermenter and sterilized by heating at 121°C for30 min. The medium is cooled, inoculated with the 10-gallon culture ofStreptomyces fragilis prepared as described above, and incubated at 26°C for44 h. During the incubation period air is supplied through a sparger at therate of 1.5-volumes of air per volume of medium per min and the mixturestirred at the rate of 150 r.p.m. for the first 12 h and at 300 r.p.m. for thefinal 32 h, 1.5 gallons of a sterilized mixture of crude lard and mineral oilscontaining mono- and diglycerides being added as needed to control foaming. The solid material present in the incubated fermentation mixture is removedby filtration and the filter cake washed with water. The washings are combinedwith the main filtrate and 110 gallons of this solution stirred with 2079.0 g ofactivated carbon for about 1 h. The carbon is removed by filtration and thefilter cake washed with deionized water. The combined filtrate and washes(136 gallons) are concentrated in vacuum to a volume of about 20 gallons.Three volumes of acetone are added to the concentrate with stirring, and theprecipitate which forms removed by filtration and the filter cake washed with75% aqueous acetone. The combined aqueous acetone filtrate and washingsis concentrated in vacuum to a volume of about 19.5 gallons, the concentrateso obtained frozen and dried from the frozen state under high vacuum. 1.0 kgof dry powder is extracted with one 10-liter portion of 90% (by volume)ethanol followed by extraction with one 2-liter portion of the same solvent.The combined extracts (about 12 L) are diluted with sufficient water to reducethe ethanol concentration to 75% by volume, and this alcoholic solutionpassed through an adsorption column prepared as described below. 3.0 kg of alumina are stirred with dilute hydrochloric acid so that the pHremains constant at 7.7. The alumina is removed, washed with water andactivated by heating at 200°C for 4 h. The alumina is stirred with 75%aqueous ethanol and packed into an adsorption column having a diameter of 4inches. The total packed volume is approximately 3500 ml. The alcoholic solution prepared above is added to the adsorption column atthe rate of 6 L/h and the percolate discorded. The column is washed with 35 Lof 75% ethanol (by volume), the washing discarded and the column finallywashed with 21 L of 50% ethanol. Some O-diazoacetyl-L-serine may be detected in the last wash solution. After the washing has been completed theadsorbed O-diazoacetyl-L-serine is eluted from the adsorption column bypassing 17.5 L of distilled water through the column. The aqueous eluate isconcentrated and frozen and the concentrate dried from the frozen stateunder high vacuum. The powder thus obtained, a O-diazoacetyl-L-serinecontent of 5.8%. 500.0 g of the material assaying 5.8% O-diazoacetyl-L-serine is dissolved in1,320 ml of water. A column of activated charcoal is prepared. A mixture of2.0 kg of activated charcoal (Darco (1-60) and 2.0 kg of diatomaceous earthis packed as a thick slurry in a 6 inch column. The pH of the water is 5.2-5.5.With this bed, a head of 4 feet of solvent is necessary to achieve a suitableflow rate. After packing, the column is washed with water for several hours tosettle and remove solubles. The solution is applied to the column with positivepressure equivalent to a head of four foot of water. One retention volume of 9L of water is then applied to the column. This is followed by a 5% acetonesolution. The total solvent flow is 36 L. The colorless eluate is discarded. Theelution front which is easily detected is a light yellowish-green solution. Thissolution is retained. The solution is concentrated by vacuum distillation until aconcentration of 20-25 mg/ml is reached. This solution is applied to a columnprepared in an identical manner as described herein and treated by the sameprocedure as the primary adsorption. The percolate is concentrated byvacuum distillation until a concentration of 60-75 mg/ml is reached. Thequantity of solution is now approximately 300 ml. Absolute alcohol (450 ml) isadded. The solution is gently warmed to complete solution and then stored at5°C for several hours. The O-diazoacetyl-L-serine which separates incrystalline form is collected and purified by recrystallization from 60-70%ethanol, is an aqueous buffer of pH 7. |
| Therapeutic Function | Antineoplastic, Antifungal |
| General Description | Pale yellow to green crystals. Used as an antifungal agent. |
| Air & Water Reactions | Very soluble in water. |
| Reactivity Profile | AZASERINE is incompatible with acids. |
| Hazard | Toxic; possible carcinogen; neoplastigenic;tumorigenic; poison; teratogen; mutagen. |
| Biological Activity | azaserine, as a naturally occurring serine derivative diazo compound, functions as a purine antagonist and structural analogue of glutamine that inhibits enzymatic activities involving in the pathways of glutamine metabolism. azaserine, an antibiotic and antitumor agent, is used as a potential antineoplastic agent in clinical studies. azaserine dampens the biosynthesis of purine via reacting with cysteine residues in the enzyme active sites. in addition, azaserine triggers dna damage by the formation of carboxymethylated bases and o6-methylguanine. |
| Safety Profile | Suspected carcinogenwith experimental carcinogenic,neoplastigenic, and tumorigenic data. Poisonby ingestion, intraperitoneal, andsubcutaneous routes. An experimentalteratogen. Other experimental reproductiveeffects. Human mutation data reported.When heated to decomposition it emitstoxic fumes of NOx. |
| in vitro | azaserine showed cytotoxicity in raji cells, which was partly due to inhibition of de novo purine biosynthesis, and the expression of o6-methylguanine-dna methyltransferase did not provide protection against cell killing, suggesting that o6-methylguanine was not a major contributor to the cytotoxic dna damage triggered by azaserine. azaserine killed the raji hypoxanthine-guanine phosphoribosyltransferas-deficient(hprt-) mex- cells. in contrast, the raji hprt+ mex- cells were more resistant to azaserine. additionally, azaserine blocked the growth of raji hprt+ mex-cells when treated with 300 μm [1]. |
| in vivo | cd-l mice and w/lew rats were injected intraperitoneally with azaserine at a dose of 10 mg/kg body weight once a week for 5 weeks. after 6 months, compared to the control rats and mice, the azaserine-treated animals had a slightly higher incidence of pancreatic atypical acinar cell nodules (aacn) and the average size of aacn of azaserine-treated animals was larger. in addition, the concentration of [14c] azaserine and/or its metabolites was lower in mouse pancreas than in rat pancreas [2]. |
| IC 50 | 7 μm: inhibits parasite growth. |
| Purification Methods | Crystallise azaserine from 90% EtOH. Also dissolve it in H2O, filter it through Supercel and add EtOH to give azaserine as pale yellow crystals. [Greenstein & Winitz The Chemistry of the Amino Acids J. Wiley, Vol 1 pp 75-76 1961, Curphey & David J Org Chem 43 4666 1978, Beilstein 4 IV 3124.] |
| references | [1]. o'driscoll, m., macpherson, p., xu, y., & karran, p. the cytotoxicity of dna carboxymethylation and methylation by the model carboxymethylating agent azaserine in human cells. carcinogenesis. 1999; 20(9): 1855-1862. [2]. b. d. roebuck, herman s. lilja, thomas j. curphey, daniel s. longnecker; pathologic and biochemical effects of azaserine in inbred wistar/lewis rats and noninbred cd-1 mice. j natl cancer inst. 1980; 65 (2): 383-389. |
AZASERINE Preparation Products And Raw materials
| Raw materials | Sodium hydroxide-->MINERAL OILS-->Ammonium nitrate-->D-Glucose monohydrate-->SOAP-->Calcium carbonate-->STREPTOMYCES |
