2353-33-5

Basic information

• Product Name: 5-Aza-2'-deoxycytidine
• Synonyms: 4-Amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one;5-Aza-2'-deoxycytidine,98+%;4-Amino-1-(2-deoxy-β-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one;Decitabine(NSC127716);Decitabine(5-aza-2'-deoxycytidine,NSC127716);5-Aza-2'-deoxycytidine (Decitabine);5-Aza-2zzhlxy-deoxycytidine (Decitabine);4-aMino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxyMethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
• CAS NO: 2353-33-5
• Molecular Formula: C₈H₁₂N₄O₄
• Molecular Weight: 228.21
• EINECS: 219-089-4
• Product Categories: analog of cytosine;Intermediates & Fine Chemicals;Pharmaceuticals;Epigenetics;Inhibitor;Deoxycytidine;Anti-cancer&immunity;Inhibitors;API;Bases & Related Reagents;Nucleotides
• Mol File: 2353-33-5.mol

Chemical Properties

• Melting Point: ~200 °C (dec.)
• Boiling Point: 370.01°C (rough estimate)
• Flash Point: 247.6 °C
• Appearance: White to Off-white/Powder
• Density: 1.3771 (rough estimate)
• Refractive Index: 1.6590 (estimate)
• Storage Temp.: −20°C
• Solubility: acetic acid/water (1:1): 50 mg/mL
• PKA: 14.02±0.60(Predicted)
• Stability: Stable. May be light or air sensitive. Incompatible with strong oxidizing agents.
• Merck: 14,2853
• BRN: 617982
• CAS DataBase Reference: 5-Aza-2'-deoxycytidine(CAS DataBase Reference)
• NIST Chemistry Reference: 5-Aza-2'-deoxycytidine(2353-33-5)
• EPA Substance Registry System: 5-Aza-2'-deoxycytidine(2353-33-5)

Safety Data

• Hazard Codes: Xn,Xi,T
• Statements: 22-36/37/38-68-61
• Safety Statements: 26-36-36/37
• WGK Germany: 3
• RTECS: XZ3012000
• F: 10-34
• Hazardous Substances Data: 2353-33-5(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
5-Aza-2'-deoxycytidine is used as a demethylating agent for the treatment of myelodysplastic syndromes (MDS), a set of hematologic disorders affecting the bone marrow that result in ineffective formation and development of blood cells. Patients with MDS have a high risk of progressing to acute myeloid leukemia (AML). Decitabine has shown to improve the quality of life and potentially modify the disease progression in these patients.
Used in Cancer Research:
5-Aza-2'-deoxycytidine is used as a demethylating agent in breast cancer cell lines, chromatin, DNA, and the promoter region of the p16 gene. It has been found to inhibit the growth of pancreatic endocrine tumor cell lines, making it a valuable tool in cancer research for understanding the epigenetic mechanisms involved in tumor growth and progression.
Used in Drug Development:
Decitabine is a potent inhibitor of DNA methylation with an IC50 of 438 nM in HL-60 cells and 4.38 nM in KG1a cells, respectively. Its ability to inhibit DNA methylation makes it a promising candidate for the development of new drugs targeting various types of cancer and other diseases related to abnormal DNA methylation patterns.

Indications and Usage

5-Aza-2’-deoxycytidine, also known as decitabine or 2'-deoxy-5-azacytidine, is a cell cycle S phase-specific drug used to treat myelodysplastic syndromes (MDS.)

Mechanisms of Action

Demethylating agents can regulate gene expression by activating tumor suppressor genes and enhancing the differentiation of genes, which help treat MDS. 5-Aza-2’-deoxycytidine is a natural andenosine analogue of 2′-deoxycytidine, known to the be strongest methylation specific inhibitor of DNA. After phosphorylation it can inhibit DNA methyltransferase, reducing DNA methylation, leading to demethylation of tumor cells, which can restore the normal functioning of genes, thus inhibiting tumor cell proliferation and preventing the occurrence of drug resistance. 5-Aza-2’-deoxycytidine inhibits DNA methylation in vitro, but does not affect its synthesis. Moreover, non-proliferating cells are not sensitive to it. 5-Aza-2’-deoxycytidine has anti-tumor activity and is characterized by a dual mechanism based on dose differences. At high concentrations it is cytoxic, while at low concentrations it is demethlyating.

Side Effects

Neutropenia, thrombocytopenia, anemia, vomiting, fatigue, fever, cough, nausea, constipation, diarrhea, hyperglycemia, and heat induced neutrophil. Large doses may cause neurotoxicity, manifested as lethargy, aphasia, hemiplegia, etc., which disappears after stopping.

Toxicity grading

high

Acute toxicity

Intravenous – mouse LD50: 22 mg/kg; peritoneal – mouse LD50: 190 mg/kg

Flammability Hazardous characteristics

Combustible; produces toxic nitrogen oxide fumes.

Storage characteristics

Ventilated, cold, and dry; store away from raw food materials.

Fire extinguishing agent

dry powder, foam, sand, carbon dioxide, water mist.

Originator

Pharmachemie (Netherlands)

Air & Water Reactions

Probably light and air sensitive. Water soluble. Decomposes in aqueous solution at a rate that depends on pH: at pH 7 the drug is more stable than at pH 9, but is less stable than at pH 6. At pH 7 and 99°F, approximately 7% conversion occurs in 1 hour .

Reactivity Profile

5-Aza-2'-deoxycytidine is an aminoalcohol. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

Fire Hazard

Flash point data for 5-Aza-2'-deoxycytidine are not available. 5-Aza-2'-deoxycytidine is probably combustible.

Biological Activity

Cytosine analog that once incorporated into DNA acts as a suicide substrate for DNA methyltransferase. Inhibits DNA methyltransferase and results in DNA hypomethylation and activation of silent genes. Chemotherapeutic agent; suppresses growth of human tumor cell lines. Demethylates differentiation-related genes; reverses embryonic stem cell differentiation.

Biochem/physiol Actions

Primary TargetDNA methyltransferase inhibitor

Clinical Use

Antineoplastic antimetabolite agent:Treatment of acute myeloid leukaemia

Safety Profile

Poison by intravenous route.Human mutation data reported. When heated todecomposition it emits toxic fumes of NOx.

Synthesis

Silylated 5-aza-cytosine (28) was condensed with 9- fluorenylmethoxycarbonyl (Fmoc) protected 2-deoxy-1-chlororibose (27) with tin chloride (IV) in dichloroethane (Scheme 4). The coupled product 29 was de-protected with excess triethylamine in dry pyridine to give decitabine (IV) in 36% yield after separation from its corresponding αisomer.

Drug interactions

Potentially hazardous interactions with other drugsAntipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Metabolism

The exact route of metabolism and elimination is unknown but thought to be through deamination by cytidine deaminase in the liver, kidney, intestinal epithelium and blood to form inactive metabolites.

References

1) Bender et al. (1998), Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines; Cancer Res., 58 95 2) El-Serafi et al. (2011), Epigenetic modifiers influence lineage commitment of human bone marrow stromal cells: Differential effects of 5-aza-deoxycytidine and trichostatin A; Differentiation, 81 35

Upstream product

• 69304-64-9 N-(formylamidino)-N'-β-D-2-deoxyribofuranosylurea 
• 135567-49-6 decitabine monohydrate 
• 931-86-2 5-azacytosine 
• 21740-23-8 3,5-O-bis(4-chlorobenzoyl)-2-deoxy-α-D-ribofuranosyl chloride 
• 1034301-08-0 1-(3,5-di-O-p-chlorobenzoyl-2-deoxy-β-D-ribofuranosyl)-5-azacytosine 
• 1207459-15-1 1-O-acetyl-3,5-di-O-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose 
• 52523-35-0 2-(trimethylsilylamino)-4-(trimethylsilyloxy)-s-triazine 
• 1140891-02-6 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-1,3,5-triazin-2(1H)-one 
• 22432-93-5 3',5'-O-acetyl-2'-deoxy-5-azacytidine 
• 3601-89-6 Hoffer's chlorosugar 
• 951-78-0 2'-deoxyuridine 
• 80184-05-0 1-chloro-2-deoxy-D-ribofuranose 
• 17039-17-7 2-deoxy–α-D-ribose 1-phosphate 
• 2353-33-5 5-aza-2'-deoxycytidine 

Downstream Products

• 10302-79-1 2'-deoxy-3',5'-di-O-p-toluoyl-5-azacytidine 
• 183016-22-0 2'-deoxy-5'-O-p-toluoyl-5-azacytidine 
• 66642-55-5 2'-deoxy-β-D-5-azacytidine 5'-monophosphate 
• 431890-07-2 2'-deoxy-N₄-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine 
• 431890-06-1 [4-Oxo-5-((2R,4S,5R)-4-trimethylsilanyloxy-5-trimethylsilanyloxymethyl-tetrahydro-furan-2-yl)-4,5-dihydro-[1,3,5]triazin-2-yl]-carbamic acid 2-(4-nitro-phenyl)-ethyl ester 
• 431890-08-3 (5-{(2R,4S,5R)-5-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-tetrahydro-furan-2-yl}-4-oxo-4,5-dihydro-[1,3,5]triazin-2-yl)-carbamic acid 2-(4-nitro-phenyl)-ethyl ester 
• 117436-80-3 Isobutyric acid 3-{(2R,4S,5R)-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-tetrahydro-furan-2-yl}-8-isobutyryl-7-isobutyryloxy-2-oxo-2,3,4,6,7,8-hexahydro-imidazo[1,2-a][1,3,5]triazin-6-yl ester 
• 117399-77-6 5,6-dihydro-5-azacytidine phosphoramidite 
• 117436-81-4 C₅₆H₆₉N₆O₁₉P 
• 931-86-2 5-azacytosine 
• 452-51-7 D-2-deoxyribose 
• 1423539-59-6 C₂₁H₂₇N₅O₇ 
• 1423539-61-0 C₂₁H₂₇N₅O₇ 
• 1423539-65-4 C₂₅H₂₇N₅O₇ 

Relevant articles and documents

Decitabine intermediate compound VI

The invention belongs to the technical field of chemical synthesis, and provides a decitabine intermediate compound. A preparation route of the decitabine intermediate compound comprises the followingsteps: taking an oxymethyl compound of a hydroxyl group at a 1 site of 2-deoxy-D-ribose as a raw material, protecting a hydroxyl group at a 3 site and a hydroxyl group at a 5 site respectively, then performing acetylation substitution on a 1 site of sugar, and further treating to obtain the compound. The method is simple and convenient to operate, does not need special equipment, is good in product purity and high in yield, and is suitable for industrial production; decitabine is further synthesized by utilizing the compound, so that the stereoselectivity is high, and the purity isgood.

Decitabine intermediate compound V

The invention belongs to the technical field of chemical synthesis, and provides a decitabine intermediate compound. A preparation route of the decitabine intermediate compound comprises the followingsteps: taking an oxymethyl compound of 2-deoxy-D-ribose 1 site hydroxyl as a raw material, respectively protecting 3 site and 5 site hydroxyl, and further treating to obtain the compound provided by the invention. The method is simple and convenient to operate, does not need special equipment, and is good in product purity, high in yield and suitable for industrial production; and decitabine is further synthesized by utilizing the compound, so that the compound is high in stereoselectivity and good in purity.

Preparation method of decitabine

The invention belongs to the technical field of organic synthesis, and provides a preparation method of decitabine. The preparation method specifically comprises the following steps: first carrying out reflux extraction to obtain a mixture of decitabine alpha and beta isomers, and then separating the isomers by applying the supercritical fluid technology to obtain high-purity decitabine. Comparedwith the prior art, the technical method which is simple in operation process, high in separation efficiency, high in product yield, high in final product purity and suitable for industrial productionis provided.

2-deoxy-D-ribose derivative

The invention belongs to the field of medicine synthesis, and provides a 2-deoxy-D-ribose derivative (III). When the derivative (III) is used for preparing decitabine, the stereoselectivity is good, and the yield is high. The invention provides a preparation method of the derivative. The preparation method comprises the following steps: step a, carrying out oxygen methylation on 1-position hydroxyl of 2-deoxy-D-ribose; and step b, protecting hydroxyl groups at positions 3 and 5, and further carrying out sulfonation on 1-position oxymethyl. The method is simple and convenient to operate, free of special equipment, good in product purity, high in yield and suitable for industrial production.

Synthetic method of decitabine

The present invention relates to a synthetic method of decitabine, and discloses a method for synthesizing a compound as shown in a formula I, The method comprises the steps of: reacting a compound IIwith a compound III by a following reaction in a solvent under the action of TMSOTf to obtain a compound I. The synthetic method of the invention has the advantages that the raw materials are easy toobtain, the operation is safe, the conditions are mild and easy to control, and a solid product obtained by an acylation protection is easy to be crystallized and purified, which is favorable for thenext reaction and improves the selectivity of a final beta-isomer product, no further conversion to hydroxymethyl is required, the reaction step is simplified, the reaction yield of each step is good, the atomic economy is high, and the method is suitable for a large number of industrial production and the like.

Preparation method of beta-nucleoside compound

The invention provides a method for preparing beta-nucleoside or analogue thereof, comprising the following steps: 1) enabling nitrogenous base or analogue thereof to generate silylanizing reaction under the existence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), to obtain the nitrogenous base or analogue thereof protected by trimethylsilyl; 2) enabling a reaction liquid to directly perform glycosylation reaction with quintuple cyclose or hexahydric cyclose sealed by a hydroxy protection group, so as to obtain a sealed beta-nucleoside or analogue thereof; 3) performing protection groupremoval reaction, to obtain the beta-nucleoside or analogue thereof. The method disclosed by the invention is simple in operation, energy-saving and environment-friendly, a key intermediate of the beta-nucleoside or analogue thereof is prepared by a one-pot methoid, and the yield of beta configuration substance is remarkably increased, and the preparation method is suitable for industrial application.

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

The trans-2-deoxyribosylation of 4-thiouracil (4SUra) and 2-thiouracil (2SUra), as well as 6-azauracil, 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases. 4SUra revealed satisfactory substrate activity for UP and, unexpectedly, complete inertness for TP; no formation of 2′-deoxy-2-thiouridine (2SUd) was observed under analogous reaction conditions in the presence of UP and TP. On the contrary, 2SU, 2SUd, 4STd and 2STd are good substrates for both UP and TP; moreover, 2SU, 4STd and 2′-deoxy-5-azacytidine (Decitabine) are substrates for PNP and the phosphorolysis of the latter is reversible. Condensation of 2SUra and 5-azacytosine with dRib-1P (Ba salt) catalyzed by the accordant UP and PNP in Tris·HCl buffer gave 2SUd and 2′-deoxy-5-azacytidine in 27% and 15% yields, respectively. 6-Azauracil and 6-azathymine showed good substrate properties for both TP and UP, whereas only TP recognizes 2-thio-6-azathymine as a substrate. 5-Phenyl and 5-tert-butyl derivatives of 6-azauracil and its 2-thioxo derivative were tested as substrates for UP and TP, and only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed.

Development of an immobilized biocatalyst based on Bacillus psychrosaccharolyticus NDT for the preparative synthesis of trifluridine and decytabine

The immobilization of Bacillus psychrosaccharolyticus nucleoside 2′-deoxyribosyltransferase was deeply investigated and finally optimized. The best immobilization procedure resulted to be ionic adsorption on PEI 600 Da agarose followed by crosslinking with 70% oxidized dextran (20 kDa). The percentage of recovered activity was further improved (from 21% to 33%) by the addition of 20% glycerol to the immobilization mixture. The resulting biocatalyst showed a stability profile similar to that of the soluble enzyme and it was used for the preparative synthesis of trifluridine and decytabine obtaining conversions ranging from 50% to 76%.

Decitabine a process for the preparation of

The invention discloses a preparation method of decitabine. The preparation method comprises the steps: oxygen methylation of 1st-site hydroxyl of 2-deoxy-D-ribose; protection for hydroxyls on a 3rd site and a 5th site; acylation of 1st-site oxygen methyle; activation of 5-azacytosine; and coupled reaction of protected 2-deoxy-D-ribose and the activated 5-azacytosine, purification of a coupling product; deprotection; and obtaining of a target product. According to the preparation method, the purity of the decitabine is improved, the purification steps of a final product are simplified, and the product cost is lowered.

A SITAR hamanaka process for the preparation of intermediates

The invention discloses a preparation method of a decitabine intermediate compound 1-acetoxyl-2-deoxidized-3,5-bi-O-fluorene methyl cyslohexyl-D-ribofuranose. The structural formula of the compound is shown in img file='DDA0000455164900000011.TIF' wi='648' he='304'/, and the preparation method comprises the following steps: o-methylation of 2'-deoxidized-D-ribose 1-bit hydroxyl; b) protection of 3,5-bit hydroxyl; and c) acylation of 1-bit-O-methyl. The invention also discloses a method for preparing decitabine employing the intermediate as a raw material.