General Description
White crystalline powder.
Reactivity Profile
5-AZACYTIDINE(320-67-2) is sensitive to light (may discolor). 5-AZACYTIDINE(320-67-2) is sensitive to oxidation. 5-AZACYTIDINE(320-67-2) is unstable in solution. 5-AZACYTIDINE(320-67-2) undergoes hydrolysis in aqueous buffers. This chemical is incompatible with strong oxidizers.
Air & Water Reactions
Slightly water soluble. Unstable in solution.
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.
Fire Hazard
Flash point data for this chemical are not available; however, 5-AZACYTIDINE is probably combustible.
First aid
Eyes: First check the victim for contact lenses
and remove if present. Flush victim’s eyes with water or
normal saline solution for 20 to 30 minutes while simultaneously
calling a hospital or poison control center. Do not
put any ointments, oils, or medication in the victim’s eyes
without specific instructions from a physician. Immediately
transport the victim after flushing eyes to a hospital even if
no symptoms (such as redness or irritation) develop. Skin:
Immediately flood affected skin with water while removing
and isolating all contaminated clothing. Gently wash all
affected skin areas thoroughly with soap and water. If
symptoms such as redness or irritation develop, immediately
call a physician and be prepared to transport the
victim to a hospital for treatment. Inhalation: Immediately
leave the contaminated area; take deep breaths of fresh air.
IMMEDIATELY call a physician and be prepared to transport
the victim to a hospital even if no symptoms (such as
wheezing, coughing, shortness of breath, or burning in the
mouth, throat, or chest) develop. Provide proper respiratory
protection to rescuers entering an unknown atmosphere.
Whenever possible, SCBA (SCBA) should be used; if not
available, use a level of protection greater than or equal to
that advised under Protective Clothing. INGESTION: Do
not induce vomiting. If the victim is conscious and not convulsing,
give 1 or 2 glasses of water to dilute the chemical
and immediately call a hospital or poison control center. Be
prepared to transport the victim to a hospital if advised by
a physician. If the victim is convulsing or unconscious, do
not give anything by mouth, ensure that the victim’s airway
is open and lay the victim on his/her side with the head
lower than the body. Do not induce vomiting. Immediately
transport the victim to a hospital.
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.
Chemical Properties
White crystalline solid or powder.
Chemical Properties
White-to-Off-White Crystalline Solid
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.
Uses
A potent growth inhibitor and cytotoxic agent. It acts as a demethylating agent by inhibiting DNA methyltransferase
Uses
Antineoplastic;'Antimetabolite
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.
Brand name
Vidaza (Pharmion).
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.
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
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).
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%.
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
