5-Azacytidine

Iupac Name：4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,
3,5-triazin-2-one

Molecular Weight：244.20468

Modify Date.: 2022-11-29 10:27

Introduction: Azacytidine also referred to as Azacytidine and 5-azacytidine (brand name: Vidaza) is an anti-cancer chemotherapy medication. The drug is classified as demethylation and antimetabolite agent. Azacytidine acts by inhibiting the growth and proliferation of cancer cells in the body. The drug is indicated for the treatment of specific types of blood cell disorders and bone marrow cancers. View more+

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1. Names and Identifiers

1.1 Name: 5-Azacytidine
1.2 Synonyms: [14C]-Azacitidine 1,3,5-triazin-2(1H)-one, 4-amino-1-b-D-ribofuranosyl- 1,3,5-Triazin-2(1H)-one, 4-amino-1-Β-D-ribofuranosyl- 4-amino-1-(b-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one 4-Amino-1-(Β-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one 4-Amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,3,5-triazin-2(1H)-one 4-Amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,5-triazin-2(1H)-on 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,5-triazin-2(1H)-one 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxyméthyl)tétrahydrofuran-2-yl]-1,3,5-triazin-2(1H)-one 4-Amino-1-b-D-ribofuranosyl-1,3,5-triazine-2(1H)-one 5 AZC 5-AC 5-AC-15N4 5-AZAC 5'-azacytidine 5-AZCR Antibiotic U 18496-15N4 Azacitidine Azacitidine-15N4 azacytidine Azacytidine, 5- Azacytidine-15N4 AzGR EINECS 206-280-2 Ladakamycin LadakaMycin-15N4 LedakaMycin-15N4 L-Β-Ribofuranosyl-5-azacytosine MFCD00006539 mylosar Mylosar-15N4 NSC 102816-15N4 NSC 103-627-15N4 Vidaza

1.3 CAS No.: 320-67-2

1.4 CID: 9444

1.5 EINECS(EC#): 206-280-2

1.6 Molecular Formula: C8H12N4O5 (isomer)

1.7 Inchi: InChI=1S/C8H12N4O5/c9-7-10-2-12(8(16)11-7)6-5(15)4(14)3(1-13)17-6/h2-6,13-15H,1H2,(H2,9,11,16)/t3-,4-,5-,6-/m1/s1

1.8 InChkey: NMUSYJAQQFHJEW-KVTDHHQDSA-N

1.9 Canonical Smiles: C1=NC(=NC(=O)N1C2C(C(C(O2)CO)O)O)N

1.10 Isomers Smiles: C1=NC(=NC(=O)N1[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O)N

2. Properties

2.1 Density: 2.08

2.1 Melting point: 228-230℃

2.1 Boiling point: 534.5 oC at 760 mmHg

2.1 Refractive index: 1.823

2.1 Flash Point: 277 oC

2.1 Precise Quality: 244.08100

2.1 PSA: 143.72000

2.1 logP: -2.58680

2.1 Solubility: 0.5-1.0 g/100 mL at 21 ºC

2.2 Appearance: White to Off-white lyophilized powder

2.3 Storage: Store at -20°C.

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

2.5 Chemical Properties: White crystalline solid or powder.

2.6 Color/Form: Powder

2.7 Decomposition: When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

2.8 pKa: 13.46±0.70(Predicted)

2.9 Water Solubility: H2O: 0.5-1.0 g/100 mL at 21 oC

2.10 Spectral Properties: UV max (water): 241 nm (epsilon 8767); (0.01 N HCl): 249 nm (epsilon 3077); (0.01 N KOH): 223 nm (epsilon 24200)
Optical rotation: + 39 degrees @ 25 deg C (c = 1 in water)

2.11 Stability: Bulk: Samples of 5- azacitidine and 5- azacitidine hydrate were found to be stable at 25 °C and 60 °C for at least 30 days. Solution: Dilute aqueous solutions of 5-azacitidine have been found to be unstable at 24 -26 ° C. A 1% aqueous solution at 5-6°C decomposes 2, 5, and 9% in 2, 8, and 24 hours respectively. At room temperature a 1% aqueous solution shows 7, 20 and 41% decomposition in 2, 8, and 24 hours respectively (UV and NMR).

2.12 StorageTemp: -20°C

3. Use and Manufacturing

3.1 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.

3.2 General Description: White crystalline powder.

3.3 Methods of Manufacturing: A mixture of 5-azacytosine (5.0 g, 44.6 mol), HMDS (6.3 mL, 29.8 mol), and TMSCl (6 mL, 47.3 mmol) in acetonitrile (78 mL) was heated to reflux for 20 hours under an inert atmosphere. TMS-triflate (9 mL, 50 mmol) and 1, 2, 3, 5-tetra-O-acetyl-β-D-ribofuranose (14.2 g, 44.6 mmol were added directly to the silylated 5-azacytosine in acetonitrile. The addition was performed at ambient temperature and under an inert atmosphere. The reaction mixture was maintained under stirring for 20 hours, then poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10percent, 500 mL). The resulting mixture was extracted with dichloromethane (3.x.75 mL). The combined organic extract was washed with cooled (0-5° C.) 10percent sodium bicarbonate (2.x.25 mL) and brine (2.x.25 mL), then dried over magnesium sulfate (10.0 g), filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam dissolved in methanol (120 mL) was treated with a solution of 25percent sodium methoxide in methanol (1.0 g, 4.62 mmol). Soon a white solid started to separate. The suspension was stirred at ambient temperature for 15 hours, then the solid was filtered off, washed with methanol (3.x.5 mL) and anhydrous ether (2.x.5 mL), then dried in vacuum. The crude 5-azacytidine (4.5 g, 41.3percent) was further purified from DMSO and methanol (for details see Example 4).[00122] The latter was dissolved in MeOH (240 g) and the resulting mixture was filtered (small amount of salt).[00123] 25percent MeONaMeOH (15.4 g; 0.02 mol) dissolved in MeOH (250 g) was added over 5 min.[00124] The resulting mixture is stirred at 20-25°C for 1.5 h. The crystals were filtered and washed with MeOH (300 g).[00125] The wet solid was dried under vacuum at 60°C for 15 h to give 5-azacytidine as an off white solid.[00126] Yield: 75percent, purity >99percent area by HPLC.To a solution of 2, 3, 5-tri-O-acetyl-β-D-ribofuranose-4-amino-1, 3, 5-triazine (1.0 Kg) which is dissolved in DBU (5.0 L) was added methanol (40 L) and stirred for 6 h at 20-25 °C. Filtered the solid and washed with methanol (500 mL) and suck dried for 30 min and subjected for drying under vacuum tray drier to get crude 400 g of 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one.

3.4 Potential Exposure: A growth inhibitor (DNA methyltransferaseinhibitor). A cytotoxic agent and chemotherapeuticagent used to treat angina pectoris, an ischemic heart diseasesymptom. Occupational exposure to azacitidine couldoccur among health professionals and support staff (includingcustodians) by dermal contact, inhalation, or accidentalingestion during drug preparation or administration orcleanup of medical waste, including disposal of excretionsfrom treated patients (Zimmerman et al. 1981, NIOSH2004). The National Occupational Exposure Survey (conductedfrom 1981 to 1983) estimated that 1069 healthservicesworkers, including 698 women, potentiallywere exposed to azacitidine. Azacitidine may beproduced synthetically or isolated from the bacteriumStreptoverticillium ladakanus .Incompatibilities: Azacitidine is Incompatible with oxidizers(chlorates, nitrates, peroxides, permanganates, perchlorates,chlorine, bromine, fluorine, etc.); contact may causefires or explosions. Keep away from alkaline materials,strong bases, strong acids, oxoacids, epoxides. Contact withalkali metals, nitrides, and strong reducing agents such ashydrides may form flammable and/or toxic gases. May reactwith anhydrides forming acids and esters, generating noticeableheat, and also with oxoacids and carboxylic acids toform esters plus water, but the heat of reaction in the lattercase typically is low. Keep away from isocyanates andepoxides; may initiate their polymerization. Azacitidine issensitive to light and oxidation and unstable in solution. Itundergoes hydrolysis in aqueous buffers.

3.5 Shipping: UN3249 Medicine, solid, toxic, n.o.s., HazardClass: 6.1; Labels: 6.1-Poisonous materials.

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

3.7 Waste Disposal: It is inappropriate and possiblydangerous to the environment to dispose of expired orwaste drugs and pharmaceuticals by flushing them downthe toilet or discarding them to the trash. Household quantitiesof expired or waste pharmaceuticals may be mixedwith wet cat litter or coffee grounds, double-bagged inplastic, discard in trash. Larger quantities shall carefullytake into consideration applicable DEA, EPA, and FDAregulations. If possible return the pharmaceutical to themanufacturer for proper disposal being careful to properlylabel and securely package the material. Alternatively, thewaste pharmaceutical shall be labeled, securely packagedand transported by a state licensed medical waste contractorto dispose by burial in a licensed hazardous or toxic wastelandfill or incinerator. 5-AzacytidineSupplier

4. Safety and Handling

4.1 Symbol: GHS07;GHS08;

4.1 Hazard Codes: T

4.1 Signal Word: DANGER

4.1 Risk Statements: R45;R46;R22

4.1 Safety Statements: S53;S22;S36/37/39;S45

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

4.2 Hazard Declaration: H302; H350

4.2 DisposalMethods: SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

4.3 RIDADR: NONH for all modes of transport

4.3 Safety Profile: Confirmed carcinogenwith experimental carcinogenic,neoplastigenic, tumorigenic data. Poison byingestion, intravenous, and intraperitonealroutes. Human systemic effects byintravenous route: nausea, vomiting anddlarrhea, reduction in white cell count(luekopenia and agranulocytosis). Anexperimental teratogen. Other experimentalreproductive effects. Human mutation datareported. A skin irritant. When heated todecomposition it emits toxic fumes of NOx.

4.4 Caution Statement: P201; P308 + P313

4.4 Incompatibilities: Azacitidine is Incompatible with oxidizers(chlorates, nitrates, peroxides, permanganates, perchlorates,chlorine, bromine, fluorine, etc.); contact may causefires or explosions. Keep away from alkaline materials,strong bases, strong acids, oxoacids, epoxides. Contact withalkali metals, nitrides, and strong reducing agents such ashydrides may form flammable and/or toxic gases. May reactwith anhydrides forming acids and esters, generating noticeableheat, and also with oxoacids and carboxylic acids toform esters plus water, but the heat of reaction in the lattercase typically is low. Keep away from isocyanates andepoxides; may initiate their polymerization. Azacitidine issensitive to light and oxidation and unstable in solution. Itundergoes hydrolysis in aqueous buffers.

4.5 WGK Germany: 3

4.5 RTECS: XZ3017500

4.5 Protective Equipment and Clothing: A skin irritant.

4.6 Skin, Eye, and Respiratory Irritations: A skin irritant.

4.7 Safety: Confirmed carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic data. Poison by ingestion, intravenous, and intraperitoneal routes. Human systemic effects by intravenous route: nausea, vomiting and diarrhea, 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 NO_x.
Hazard Codes:?T
Risk Statements: 45-46-22?
R45:May cause cancer.?
R46:May cause heritable genetic damage.?
R22:Harmful if swallowed.
Safety Statements: 53-22-36/37/39-45
S53:Avoid exposure - obtain special instructions before use.?
S22:Do not breathe dust.?
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection.?
S45:In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)
WGK Germany: 3
RTECS of Azacitidine (CAS NO.320-67-2): XZ3017500

4.8 Specification: ? Azacitidine (CAS NO.320-67-2), its Synonyms are 4-Amino-1-beta-D-ribofuranosyl-1,3,5-traizin-2(1H)-one ; 4-Amino-1-beta-D-ribofuranosyl-s-triazin-2(1H)-one ; 5-Azacytidine ; Azacitidina ; 1,3,5-Triazin-2(1H)-one, 4-amino-1-beta-D-ribofuranosyl- ; 2-(beta-D-Ribofuranosyl)-4-amino-1,3,5-triazin-2-one ; s-Triazin-2(1H)-one, 4-amino-1-beta-D-ribofuranosyl- (8CI) . It is white-to-off-white crystalline solid.

4.9 Toxicity: Oral-mouse LD50: 572 mg/kg; peritoneal-mouse LD50: 68 mg/kg

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Carcinogenicity, Category 1B

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H302 Harmful if swallowed H350 May cause cancer
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection.
Response	P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth. P308+P313 IF exposed or concerned: Get medical advice/ attention.
Storage	P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

View all

6. NMR Spectrum

13C NMR : in DMSO-d6

13C NMR : Predict

1H NMR : 400 MHz in DMSO-d6

1H NMR : Predict

Predict 1H proton NMR

IR : KBr disk

IR : Nujol

7. Synthesis Route

320-67-2Total: 9 Synthesis Route

6974-32-9 228 Suppliers

320-67-2 263 Suppliers

Literatures:
US2014/135490 A1, ; Page/Page column ;
Yield: null

56787-28-1 1 Suppliers

320-67-2 263 Suppliers

Literatures:
Vujjini, Satish Kumar; Varanasi, Ganesh; Arevelli, Srinivas; Kandala, Sreenatha Charyulu; Tirumalaraju, Satyanarayana Raju; Bandichhor, Rakeshwar; Kagga, Mukkanti; Cherukupally, Praveen Organic Process Research and Development, 2013 , vol. 17, # 2 p. 303 - 306
Yield: ~75%

10302-78-0 13 Suppliers

320-67-2 263 Suppliers

Literatures:
SICOR INC.; BIGATTI, Ettore; LUX, Giovanna; PAIOCCHI, Maurizio; GIOLITO, Andrea; TOSI, Simone Patent: WO2010/17374 A1, 2010 ; Location in patent: Page/Page column 18 ;
Yield: ~75%

View all

8. Precursor and Product

precursor:

28708-32-9

65126-88-7

14215-97-5

52523-35-0

10302-78-0

13035-61-5

931-86-2

6974-32-9

56787-28-1

product :

65370-90-3

9. Other Information

9.0 Merck: 14,887

9.1 BRN: 620461

9.2 Description: Azacytidine also referred to as Azacytidine and 5-azacytidine (brand name: Vidaza) is an anti-cancer chemotherapy medication. The drug is classified as demethylation and antimetabolite agent. Azacytidine acts by inhibiting the growth and proliferation of cancer cells in the body. The drug is indicated for the treatment of specific types of blood cell disorders and bone marrow cancers.

9.3 Indication: Azacytidine is prescribed for treating patients with secondary types of myelodysplastic syndrome, including refractory anemia that presents in the form of ringed sideroblasts (especially if it necessitates transfusion), or it presents itself alongside thrombocytopenia or neutropenia. Also, it is used in treating refractory anemia accompanied by excess blasts, refractory anemia characterized by excess blasts in transition (currently classified as chronic myelogenous leukemia that is accompanied by multilineage dysplasia), and acute myelomonocytic leukemia.

9.4 Contraindications: Azacytidine is contraindicated in patients who have acute malignant hepatic tumors or known hypersensitivity to the drug or mannitol.

9.5 Dosage: For treatment of patients with myelodysplastic syndrome, the initial dose is 75mg/m2 administered intravenously or subcutaneously in daily doses for 7 days in 4-week intervals. The recommended maintenance dose may be increased to 100mg/m2 if there are no noteworthy effects after 2 treatment cycles and if the patient does not experience additional toxicity other than vomiting and nausea.
Patients should undergo treatment that lasts for a minimum of 4 cycles. However, a partial or complete response may necessitate additional cycles other than the recommended 4 cycles. Treatment should not be discontinued if the patient is experiencing positive outcomes from the therapy.

9.6 Mechanism of Action: 5-Azacytidine is a chemical analog that is closely linked with the cytosine nucleoside in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Azacytidine influences antineoplastic activity through two main mechanisms; suppression of DNA methyltransferase when administered in low doses, which results in hypomethylation of DNA, and unmediated cytotoxicity in anomalous hematopoietic cells present in the bone marrow by its integration into RNA and DNA at high doses which causes the death of the cells.
Since Azacytidine is considered a ribonucleoside, it integrates itself into RNA to a greater extent than DNA. The integration into RNA results in the dissimulation of malfunctioning methylation, polyribosomes, and recipient function of replicated RNA, and suppression of protein production.
The integration of Azacytidine into DNA results in a covalent bond that is characterized by DNA methyltransferases, which inhibits DNA synthesis and resultant cytotoxicity.

9.7 Elimination: Intravenous administration of the radioactive form of the drug to cancer patients results in 85% elimination of Azacytidine through urinary excretion. Fecal excretion of the radioactive dose takes place in <1% of the administered drug in 3 days. The mean elimination of radioactivity through urine accounts for 50% of 14C-azacytidine administration.

9.8 Adverse reactions: Common side effects associated with Azacytidine in more than 30% of the patients include low white blood cell count, fever, vomiting, low platelet count, anemia, and nausea. At nadir, 10-17days of chemotherapy cycles, one may also experience petechiae, ecchymosis, constipation, redness at the injection site and fatigue.
Other side effects associated with Azacytidine in about 10-29% of the patients may include insomnia, depression, itching, upper respiratory infection, hypokalemia, anxiety, skin rash, abdominal pain, weight loss, nosebleed, chest pain, swelling on the ankles, dizziness, confusion, back pain, sore throat, poor appetite, headache, myalgia and arthralgia, pain at the injection site, chills, weakness, shortness of breath and coughs.
It is important to contact health care provider if one is experiencing diarrhea (4-6 episodes in 24 hours). A patient should also contact the doctor in case he/she has nausea that interferes with their ability to eat. If one has bloodstained urine, constipation that persists regardless of laxative use, extreme fatigue, tarry or bloodstained stools, vomiting (4-5 episodes in a span of 24 hours), signs of infection such as productive coughs or painful urination, and inability to eat or take fluids for more than 24 hours.

9.9 Precautions: A patient should notify their healthcare provider if they are taking any other medications which may include herbal remedies, vitamins, and over-the-counter medications before receiving an Azacytidine prescription. A patient should not receive any vaccination or immunization while they are on Azacytidine treatment.
Breastfeeding is not recommended while one is taking this drug. A patient should also inform their healthcare provider if they are pregnant or intending to get pregnant before starting Azacytidine treatment.
Azacytidine may cause neutropenia, anemia, and thrombocytopenia. Since the drug may result in hepatotoxicity amongst patients with acute hepatic impairment, caution should be taken during the administration of Azacytidine in patients with liver disease.
Renal toxicity that may range from renal failure to increased serum creatinine and death has been reported amongst patients who have been accorded intravenous treatment with Azacytidine in combination treatment with other chemotherapeutic medications for nonMDS cases.
The drug may also result in acute tumor lysis syndrome for patients with MDS. Azacytidine poses a threat to a developing embryo/fetus based on its mechanism of action.

9.10 Description: 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. They are characterized by a hyperproliferative bone marrow, the presence of clonal blood cells with impaired morphology and maturation, and peripheral blood cytopenias resulting from ineffective blood cell production. The initial stem cell injury can be from cytotoxic chemotherapy, radiation exposure, chemical exposure, or genetic predisposition. Subsequently a clonal mutation predominates over bone marrow thereby suppressing healthy stem cells. 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. Azacitidine is an analog of cytidine in which the carbon at position 5 of the pyrimidine ring has been replaced by nitrogen. It is prepared by the ribosylation of 5-azacytosine, which is derived from the condensation of amidinourea with either an alkyl orthoformate or N,N-dimethylformamide dialkyl acetal. The antineoplastic activity of azacitidine is derived from a combination of two different mechanisms. It inhibits DNA methyltransferase, which causes demethylation or hypomethylation of DNA. In addition, it exerts direct cytotoxicity on hyperproliferating abnormal stem cells in the bone marrow. After in vivo phosphorylation, azacitidine incorporates into DNA and forms covalent adducts with cellular DNA methyltransferase, thereby depleting the cells from enzyme activity and causing hypomethylation of genomic DNA. Hypomethylation restores normal function to tumor-suppressor genes, which are responsible for regulating cell differentiation and growth. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. The recommended dosage of azacitidine is 75 mg/m² subcutaneously once daily for 7 days, and the cycle is repeated every 4 weeks. It is rapidly absorbed with peak concentrations achieved within 30 minutes of the dose. It has a bioavailability of 89% and a mean volume of distribution of 76±26 liters. Mean clearance of azacitidine is 167±49 L/hour, and the mean half-life of the parent drug is 41±8 minutes. The primary route of elimination for azacitidine and its metabolites is renal (85%), with a cumulative mean elimination half-life of 4 hours. The efficacy of azacitidine was demonstrated in a randomized, open-label, controlled clinical trial and two non-randomized trials involving 300 patients with any of the five subtypes of MDS. Approximately 14–19% of patients in these trials had an overall response rate (complete response+partial response) to azacitidine, which consisted of normalization of blood counts and decrease in bone marrow blasts percentage. The initial response was generally observed by the fifth cycle of treatment. The need for transfusions was also eliminated in responder patients. In all three studies, approximately 19% of patients met the criteria for improvement with a median duration of 195 days. The most common adverse events with azacitidine therapy include nausea, vomiting, myelosuppression, and infection. Dose-limiting toxicities include neutropenia and thrombocytopenia.

9.11 Chemical Properties: White crystalline solid or powder.

9.12 Chemical Properties: White-to-Off-White Crystalline Solid

9.13 Originator: Pharmion (US)

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

9.15 Uses: Antineoplastic;'Antimetabolite

9.16 Uses: antianginal

9.17 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.

9.18 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.

9.19 Brand name: Vidaza (Pharmion).

9.20 Therapeutic Function: Antineoplastic

9.21 Biological Functions: 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.

9.22 General Description: White crystalline powder.

9.23 Air & Water Reactions: Slightly water soluble. Unstable in solution.

9.24 Reactivity Profile: 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.

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

9.26 Biological Activity: 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.

9.27 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.

9.28 Safety Profile: 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.

9.29 Chemical Synthesis: 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).

9.30 Potential Exposure: 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.

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

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

9.33 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.

9.34 Usage: 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.

9.35 Storage Conditions: A mixture of 5-azacytosine (5.0 g, 44.6 mol), HMDS (6.3 mL, 29.8 mol), and TMSCl (6 mL, 47.3 mmol) in acetonitrile (78 mL) was heated to reflux for 20 hours under an inert atmosphere. TMS-triflate (9 mL, 50 mmol) and 1, 2, 3, 5-tetra-O-acetyl-β-D-ribofuranose (14.2 g, 44.6 mmol were added directly to the silylated 5-azacytosine in acetonitrile. The addition was performed at ambient temperature and under an inert atmosphere. The reaction mixture was maintained under stirring for 20 hours, then poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10percent, 500 mL). The resulting mixture was extracted with dichloromethane (3.x.75 mL). The combined organic extract was washed with cooled (0-5° C.) 10percent sodium bicarbonate (2.x.25 mL) and brine (2.x.25 mL), then dried over magnesium sulfate (10.0 g), filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam dissolved in methanol (120 mL) was treated with a solution of 25percent sodium methoxide in methanol (1.0 g, 4.62 mmol). Soon a white solid started to separate. The suspension was stirred at ambient temperature for 15 hours, then the solid was filtered off, washed with methanol (3.x.5 mL) and anhydrous ether (2.x.5 mL), then dried in vacuum. The crude 5-azacytidine (4.5 g, 41.3percent) was further purified from DMSO and methanol (for details see Example 4).[00122] The latter was dissolved in MeOH (240 g) and the resulting mixture was filtered (small amount of salt).[00123] 25percent MeONaMeOH (15.4 g; 0.02 mol) dissolved in MeOH (250 g) was added over 5 min.[00124] The resulting mixture is stirred at 20-25°C for 1.5 h. The crystals were filtered and washed with MeOH (300 g).[00125] The wet solid was dried under vacuum at 60°C for 15 h to give 5-azacytidine as an off white solid.[00126] Yield: 75percent, purity >99percent area by HPLC.To a solution of 2, 3, 5-tri-O-acetyl-β-D-ribofuranose-4-amino-1, 3, 5-triazine (1.0 Kg) which is dissolved in DBU (5.0 L) was added methanol (40 L) and stirred for 6 h at 20-25 °C. Filtered the solid and washed with methanol (500 mL) and suck dried for 30 min and subjected for drying under vacuum tray drier to get crude 400 g of 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one.

9.36 Storage features: Ventilated, low temperature and dry; stored separately from food materials in warehouse

9.37 Mesh: Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

9.38 Mesh Entry Terms: 1-beta-D-arabinosyl-5-azacytosine

9.39 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.

10. Computational chemical data

Molecular Weight: 244.20468g/mol
Molecular Formula: C₈H₁₂N₄O₅
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 244.08076950
Monoisotopic Mass: 244.08076950
Complexity: 384
Rotatable Bond Count: 2
Hydrogen Bond Donor Count: 4
Hydrogen Bond Acceptor Count: 5
Topological Polar Surface Area: 141
Heavy Atom Count: 17
Defined Atom Stereocenter Count: 4
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccBzuAAAAAAAAAAAAAAAAAAAASAAAAAgAAAAAAAAAAAAAAAAHgAQCAAACBThgAYBAANABgAoAAABNAAAAAEAAAABAAAIAACDEAIAiAAOQAAHBgITAADwMAIAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==

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