2-(β-D-Ribofuranosyl)-4-amino-1,3,5-triazin-2-on

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H341：Kann vermutlich genetische Defekte verursachen.

  H350：Kann Krebs verursachen.

  H372：Schädigt bei Hautkontakt und Verschlucken die Organe bei längerer oder wiederholter Exposition.

  H410：Sehr giftig für Wasserorganismen mit langfristiger Wirkung.

• Sicherheit

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P260：Dampf/Aerosol/Nebel nicht einatmen.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P273：Freisetzung in die Umwelt vermeiden.

  P301+P312：BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

5-Azacytidine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R45:Kann Krebs erzeugen.
  R46:Kann vererbbare Schäden verursachen.
  R22:Gesundheitsschädlich beim Verschlucken.

• S-Sätze Betriebsanweisung:

  S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
  S22:Staub nicht einatmen.
  S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).

• Beschreibung

  5-Azacytidine is an analog of the nucleoside cytidine which can be incorporated into DNA and RNA. 5-Azacytidine acts as an epigenetic modifier by incorporating into DNA where it irreversibly binds to DNA methyltransferases, thus inhibiting their activity.
  Azacitidine is an antineoplastic agent launched for the treatment of myelodysplastic syndrome (MDS). MDS is a group of closely related diseases caused by abnormal blood-forming stem cells of the bone marrow. Azacitidine is indicated for the treatment of all five subtypes of MDS, which consist of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

• Chemische Eigenschaften

  White crystalline solid or powder. Soluble in dimethyl sulfoxide, slightly soluble in ethanol:water (50:50), propylene glycol, polyethylene glycol; slightly soluble in water, saturated octanol aqueous solution, 5% glucose injection, N-methyl-2-pyrrolidone, 0.9% sodium chloride injection and 5% polysorbate 80 aqueous solution; insoluble in acetone, ethanol and methyl ethyl ketone.

• Originator

  Pharmion (US)

• Verwenden

  5-Azacytidine, its incorporation into RNA alters RNA synthesis and processing, and results in inhibition of protein synthesis. It has been used as a cancer chemotherapeutic agent. It is a powerful bacteriostatic, antitumor, and mutagenic agent; it also exhibits immunosuppressive, antimitotic, radioprotective, and virostatic effects.

• Verwenden

  antianginal

• Verwenden

  Antineoplastic;'Antimetabolite

• Verwenden

  A potent growth inhibitor and cytotoxic agent. It acts as a demethylating agent by inhibiting DNA methyltransferase

• Definition

  ChEBI: A N-glycosyl-1,3,5-triazine that is 4-amino-1,3,5-triazin-2(1H)-one substituted by a beta-D-ribofuranosyl residue via a N-glycosidic linkage.

• Manufacturing Process

  A mixture of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-4-methylthio-1,2- dihydro-1,3,5-triazin-2-one (0.5875 g), absolute methanol (5 ml) and a normal methanolic sodium methoxide solution (1.2 ml) is stirred at room temperature with the exclusion of atmospheric moisture (a guard tube filled with potassium hydroxide pellets is fitted to the reaction vessel). The starting compound passes into solution in the course of 5 min. The resulting solution is allowed to stand at room temperature for 45 min and then the cations are removed by passage of the solution through a column packed with 10 ml of a weakly acidic cation exchange resin in the H+ form prewashed with water and methanol. The methanolic effluent (60 ml) is evaporated under reduced pressure at 30°C, the residue is dissolved in methanol (20 ml) and the solution once again is evaporated and the 1-β-D-ribofuranosyl-4-methoxy-1,2- dihydro-1,3,5-triazin-2-one was obtained.
  The residual crude crystalline 1β-D-ribofuranosyl-4-methoxy-1,2-dihydro- 1,3,5-triazin-2-one is dissolved in a 10% solution of dry ammonia in absolute methanol (4 ml) and the whole reaction mixture is allowed to stand in a stoppered flask for 30 min at room temperature (the product begins to deposit in the course of 5 min) and for 12 h in a refrigerator at -10°C. The resulting 5-azacytidine is collected with suction, washed with methanol and dried under reduced pressure. A yield of 0.216 g (88.6%) of 5-azacytidine, that is [1-β-D-ribofuranosyl-4-amino-1,3,5-triazin-2(1H)-one], melting point 232°-234°C (dec.), is obtained.

• Trademarks

  Vidaza (Pharmion).

• Therapeutic Function

  Antineoplastic

• Biologische Funktion

  Azacitidine is given subcutaneously for the treatment of myelodysplastic syndrome, and serum levels generally are maximized within 30 minutes. The parent drug and its metabolites are excreted in the urine. Azacitidine is carcinogenic and teratogenic in rodents, and leukopenia, thrombocytopenia, and neutropenia are the most common reasons for drug discontinuation or dosage reduction.

• Allgemeine Beschreibung

  White crystalline powder.

• Air & Water Reaktionen

  Slightly water soluble. Unstable in solution.

• Reaktivität anzeigen

  5-Azacytidine is sensitive to light (may discolor). 5-Azacytidine is sensitive to oxidation. 5-Azacytidine is unstable in solution. 5-Azacytidine undergoes hydrolysis in aqueous buffers. 5-Azacytidine is incompatible with strong oxidizers.

• Brandgefahr

  Flash point data for 5-Azacytidine are not available; however, 5-Azacytidine is probably combustible.

• Biologische Aktivität

  DNA methyltransferase inhibitor. Incorporates into DNA forming covalent adducts with cellular DNMT1, depleting enzyme activity. Induces demethylation and reactivation of silenced genes. Improves the efficiency of reprogramming of stem cells.

• Biochem/physiol Actions

  5-Azacytidine is a deoxycytidine analog and a demethylating agent. It acts as a potential antineoplastic agent for acute myelogenous leukemia. 5-Azacytidine activates repressed genes by inhibiting DNA methylation. 5-Azacytidine also affects protein synthesis by altering the RNA function and stability.

• Clinical Use

  Antineoplastic agent:
  
  Treatment of people not eligible for stem cell transplants with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia

• Sicherheitsprofil

  Confirmed carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic data. Poison by ingestion, intravenous, and intraperitoneal routes. Human systemic effects by intravenous route: nausea, vomiting and dlarrhea, reduction in white cell count (luekopenia and agranulocytosis). An experimental teratogen. Other experimental reproductive effects. Human mutation data reported. A skin irritant. When heated to decomposition it emits toxic fumes of NOx.

• Synthese

  The triazine ring of azacitidine is sensitive to water; this characteristic has made the synthesis of azacitidine a challenge, especially in manufacturing at commercial scale. A number of reports have appeared in order to avoid the use of water; however, these methods all have additional problems that render them undesirable for the large scale synthesis. A recent improved synthesis is depicted in the Scheme. 5- Azacytosine (1) was bis-silylated with HMDS in the presence of (NH4)SO4 to furnish trimethylsilylated azacytosine (2) in greater than 90% yield. Coupling of silylated azacytosine 2 with 1,2,3,5-tetra-O-acetyl-b-Dribofuranose (3) in DCM in the presence of TMS-triflate provided protected 5-azacitidine 4. The acetyl groups were then removed by using NaOMe in MeOH at rt. The crude azacitidine was crystallized from DMSO/MeOH to provide pure azacitidine (I).

  

• mögliche Exposition

  A growth inhibitor (DNA methyltransferase inhibitor). A cytotoxic agent and chemotherapeutic agent used to treat angina pectoris, an ischemic heart disease symptom. Occupational exposure to azacitidine could occur among health professionals and support staff (including custodians) by dermal contact, inhalation, or accidental ingestion during drug preparation or administration or cleanup of medical waste, including disposal of excretions from treated patients (Zimmerman et al. 1981, NIOSH 2004). The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that 1069 healthservices workers, including 698 women, potentially were exposed to azacitidine. Azacitidine may be produced synthetically or isolated from the bacterium Streptoverticillium ladakanus . Incompatibilities: Azacitidine is Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Contact with alkali metals, nitrides, and strong reducing agents such as hydrides may form flammable and/or toxic gases. May react with anhydrides forming acids and esters, generating noticeable heat, and also with oxoacids and carboxylic acids to form esters plus water, but the heat of reaction in the latter case typically is low. Keep away from isocyanates and epoxides; may initiate their polymerization. Azacitidine is sensitive to light and oxidation and unstable in solution. It undergoes hydrolysis in aqueous buffers.

• Carcinogenicity

  Azacitidine is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

• Stoffwechsel

  Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Faecal excretion accounted for <1% of administered radioactivity over three days. Mean excretion of radioactivity in urine following SC administration of [14C]-azacitidine was 50%.

• Lager

  Room temperature

• Versand/Shipping

  UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

• Inkompatibilitäten

  Azacitidine is Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Contact with alkali metals, nitrides, and strong reducing agents such as hydrides may form flammable and/or toxic gases. May react with anhydrides forming acids and esters, generating noticeable heat, and also with oxoacids and carboxylic acids to form esters plus water, but the heat of reaction in the latter case typically is low. Keep away from isocyanates and epoxides; may initiate their polymerization. Azacitidine is sensitive to light and oxidation and unstable in solution. It undergoes hydrolysis in aqueous buffers.

• Waste disposal

  It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

• Einzelnachweise

  1) Giraldo et al. (2011), Inhibition of DNA Methylation in somatic cells ; Methods Mol. Biol., 791 145 2) Brueckner et al. (2005), Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA Methyltransferases; Cancer Res., 65 6305 3) Mikkelsen et al. (2008), Dissecting direct reprogramming through integrative genomic analysis; Nature, 454 49 4) Qian et al. (2011), 5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extra cellular regulated kinase; Stem Cells Dev., 21 67 5) Kiziltepe et al. (2007), 5-Azacytidine, a DNA Methyltranserase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells; Mol. Cancer Ther., 6 1718

5-Azacytidine Upstream-Materialien And Downstream Produkte

2-(β-D-Ribofuranosyl)-4-amino-1,3,5-triazin-2-on Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(655)Suppliers

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