320-67-2 Usage
Uses
Used in Cancer Treatment:
5-Azacytidine is used as an antineoplastic agent for the treatment of myelodysplastic syndrome (MDS), a group of closely related diseases caused by abnormal blood-forming stem cells of the bone marrow. It 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.
Used in Bacteriostatic Applications:
5-Azacytidine is used as a bacteriostatic agent due to its powerful antitumor and mutagenic properties. It exhibits immunosuppressive, antimitotic, radioprotective, and virostatic effects, making it a versatile compound in the field of medicine.
Used in Epigenetic Modification:
As an epigenetic modifier, 5-Azacytidine is used to alter RNA synthesis and processing, which results in the inhibition of protein synthesis. This makes it a valuable tool in the study and treatment of various diseases, including cancer.
Used in Pharmaceutical Industry:
5-Azacytidine, under the brand name Vidaza, is used in the pharmaceutical industry as a potent growth inhibitor and cytotoxic agent. It is an essential component in the development of cancer chemotherapeutic drugs and treatments.
Used in Research and Development:
5-Azacytidine is used as a research tool in the field of molecular biology and genetics. Its ability to inhibit DNA methyltransferase activity makes it a valuable compound for studying the role of DNA methylation in gene expression and regulation.
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.
Contraindications
Azacytidine is contraindicated in patients who have acute malignant hepatic tumors or known hypersensitivity to the drug or mannitol.
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.
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.
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.
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.
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.
Originator
Pharmion (US)
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.
Therapeutic Function
Antineoplastic
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.
Air & Water Reactions
Slightly water soluble. Unstable in solution.
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.
Fire Hazard
Flash point data for 5-Azacytidine are not available; however, 5-Azacytidine is probably combustible.
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.
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
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.
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).
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.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Carcinogenicity
Azacitidine is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Metabolism
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%.
Shipping
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials.
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.
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.
References
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
Check Digit Verification of cas no
The CAS Registry Mumber 320-67-2 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 3,2 and 0 respectively; the second part has 2 digits, 6 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 320-67:
(5*3)+(4*2)+(3*0)+(2*6)+(1*7)=42
42 % 10 = 2
So 320-67-2 is a valid CAS Registry Number.
InChI:InChI=1/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
320-67-2Relevant articles and documents
An improved and scalable process for the synthesis of 5-azacytidine: An antineoplastic drug
Vujjini, Satish Kumar,Varanasi, Ganesh,Arevelli, Srinivas,Kandala, Sreenatha Charyulu,Tirumalaraju, Satyanarayana Raju,Bandichhor, Rakeshwar,Kagga, Mukkanti,Cherukupally, Praveen
, p. 303 - 306 (2013)
An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine (1), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approach used to streamline the process into a very robust and practical manufacturing process are described.
Synthesis, Hydrolytic Stability, and Antileukemic Activity of Azacytidine Nucleoside Analogs
Bozhok,Kalinichenko,Kuz’mitskii,Golubeva
, p. 804 - 809 (2016)
New azacytidine nucleoside analogs with modified carbohydrate moieties were synthesized. Screening identified a highly active 2′-fluoro-containing azacytidine analog that could potentially be of interest as an agent for treating acute myelogenous leukemia and myelodysplastic syndrome.
Azacytidine methylate substance and preparation method, pharmaceutical composition and application thereof
-
Paragraph 0050-0052, (2020/01/14)
The invention discloses an azacytidine methylate substance and a preparation method, a pharmaceutical composition and application thereof. The molar ratio of azacytidine to methanol in the azacytidinemethylate substance is 1 to (0.4 to 1.0), preferably, the molar ratio is 1 to (0.4 to 0.8), much preferably, the molar ratio is 1 to (0.4 to 0.6), and especially and preferably, the molar ratio of 1to 0.5. The azacytidine methylate substance has high solubility and is soluble in water and can be used as a raw drug for azacytidine freeze-dried preparations.
Preparation method of azacitidine (by machine translation)
-
Paragraph 0024; 0027; 0028; 0031; 0032; 0035; 0036; 0039, (2019/10/01)
The invention belongs to the field, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: 5 - aza cytidine and trimethylchlorosilane are reacted, and the azacitidine intermediate I is 70 - 80 °C dissolved, and 2 hours is reacted with 1 - chlorine -2, 3, 5 - three - O O-p-chlorobenzoyl - β-D - ribose under the catalysis of boron trifluoride. the reaction is finished, washed, dried, filtered and filtered, and the filtrate is distilled under reduced pressure to obtain the azacitidine intermediate II; and the method, the method comprises the following steps. The azacitidine intermediate II is purified by ammonia alcoholysis to obtain the azacitidine with high purity by purifying the crude azacitidine crude product. The method has the advantages of mild reaction conditions, short reaction time, high yield, and suitability for industrial production. (by machine translation)
Method for preparing azacitidine by high-purity and low-calcination residue
-
Paragraph 0014; 0043; 0046-0048; 0051-0053; 0056-0058;, (2019/10/01)
The invention relates to the field of a pharmaceutical synthesis technology, and discloses a method for synthesizing azacitidine. The method improves the quality and product purity of azacitidine, andthe reaction conditions are easy to control and reduce the production cost, and the method is suitable for industrial preparation.
Preparation method of azacitidine
-
Paragraph 0009; 0028-0043, (2019/02/19)
The invention relates to a preparation method of azacitidine. According to the method, the azacitidine is prevented from making contact with water, degradation of the azacitidine is reduced, the operation is simple, and yield and purity are greatly increased. In addition, in the further purification process of the azacitidine, ethyl alcohol is used as a crystal transformation solvent, the cost isgreatly reduced, and the method is more suitable for industrial application.
A new process for deprotection of acetyl and benzoyl groups in synthesis of azacitidine
Kumar, Srujana Suneel,Sethuraman
, p. 1521 - 1524 (2018/06/12)
4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one or azacitidine is a promising DNA demethylation inhibitor used for the treatment of myloneplastic, bone cancer and breast cancer. An efficient, cost-effective and convenient manufacturing process for the synthesis of azacitidine is described. The present research relates to the synthesis, deprotection, isolation and purification of azacitidine (1). In this process, more particularly 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is used as deprotection reagent for deprotection of O-acetyl, O-benzoyl to acquire azacitidine (1). The new process allows for the reliable and efficient production of drug substance similar overall yield. The new improved process has merits including enantiomeric purity, better crystallization and the product complies with the requirements of USP30.
SYNTHESIS OF NUCLEOSIDES
-
Paragraph 0051, (2014/05/20)
A process for the preparation of nucleosides, derivatives and analogues thereof by coupling reaction of a protected suitable nitrogeneous purine or pyrimidine base, a derivative or analogue thereof and a protected suitable sugar in the presence of SnCl4 comprising the removal of SnCl4 by adding DMSO directly into the reaction mixture is described. Preferably said process is used for the preparation of antiviral and antitumor agents having a nucleoside or nucleoside-like structure, still more preferably for the preparation of azacytidine, decitabine, chlorfarabine, cladribine, mizoribine. A residual tin content lower than 300 ppm is obtained with said process.
SYSTHESIS OF 5-AZACYTIDINE
-
Page/Page column 71, (2012/10/18)
Provided herein are processes for the preparation of 5-azacytidine, useful for treating, preventing, and/or managing diseases or conditions including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and myelodysplastic syndromes (MDS), wherein 5-azacytidine is represented by the structure:
THERAPEUTIC FOR HEPATIC CANCER
-
, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
