4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one

• ChemBase ID: 1130
• Molecular Formular: C8H12N4O4
• Molecular Mass: 228.20528
• Monoisotopic Mass: 228.08585488
• SMILES: O1[C@@H]([C@@H](O)C[C@@H]1n1c(=O)nc(nc1)N)CO
• Canonical SMILES: OC[C@H]1O[C@H](C[C@@H]1O)n1cnc(nc1=O)N
• InChI: InChI=1S/C8H12N4O4/c9-7-10-3-12(8(15)11-7)6-1-4(14)5(2-13)16-6/h3-6,13-14H,1-2H2,(H2,9,11,15)/t4-,5+,6+/m0/s1
• InChIKey: XAUDJQYHKZQPEU-KVQBGUIXSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
• IUPAC Traditional name: decitabine
• Brand Name: Dacogen
• Synonyms: Azadc; DAC; Dezocitidine; 5-aza-2'-deoxycytidine; decitabine; Decitabine; 2′-Deoxy-5-azacytidine; 4-Amino-1-(2-deoxy-β-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one; 5-Aza-2′-deoxycytidine; Dacogen

Database IDs

• CAS Number: 2353-33-5
• EC Number: 219-089-4
• MDL Number: MFCD00043011
• Beilstein Number: 617982
• PubChem SID: 24890797; 160964593; 46505657
• PubChem CID: 451668

CALCULATED PROPERTIES

JChem

• Acid pKa: 13.894836
• H Acceptors: 7
• H Donor: 3
• LogD (pH = 5.5): -2.1646957
• LogD (pH = 7.4): -2.164695
• Log P: -2.1646948
• Molar Refractivity: 50.6825 cm^3
• Polarizability: 19.995268 Å^3
• Polar Surface Area: 120.74 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -1.96
• LOG S: -1.62
• Solubility (Water): 5.50e+00 g/l

PROPERTIES

Physical Property

• Solubility: acetic acid: water (1:1): soluble50 mg/mL; DMSO; Sparingly soluble
• Melting Point: ~200 °C (dec.)

Safety Information

• Storage Condition: -20°C
• RTECS: XZ3012000
• European Hazard Symbols: Toxic (T)
• German water hazard class: 3
• Risk Statements: 61-22-36/37/38-68
• Safety Statements: 26-36/37
• GHS Pictograms: GHS07; GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H302-H315-H319-H335-H341-H360
• GHS Precautionary statements: P201-P261-P281-P305 + P351 + P338-P308 + P313
• Personal Protective Equipment: dust mask type N95 (US), Eyeshields, Gloves
• Storage Temperature: -20°C

Pharmacology Properties

• Target: Antimetabolites

Product Information

• Purity: ≥97%; ≥97.0% (HPLC)
• Salt Data: Free Base
• Shipped in: wet ice
• Empirical Formula (Hill Notation): C8H12N4O4

DETAILS

DrugBank - DB01262

• Drug Groups: approved; investigational
• Description: Decitabine is indicated for treatment of patients with myelodysplastic syndrome (MDS). It is a chemical analogue of cytidine, a nucleoside present in DNA and RNA. Cells in the presence of Decitabine incorporate it into DNA during replication and RNA during transcription. The incorporation of Decitabine into DNA or RNA inhibits methyltransferase thereby causing demethylation in that sequence. This adversely affects the way that cell regulatory proteins are able to bind to the DNA/RNA substrate.
• Indication: For treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups (scores ≥0.5).
• Pharmacology: Decitabine is an analogue of the natural nucleoside 2’-deoxycytidine. It functions in the same way as 5-Azacytidine. The antineoplastic activity of this drug is dependent on its intracellular conversion to its 5'-triphosphate metabolite.
• Toxicity: There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia.
• Affected Organisms: Humans and other mammals
• Biotransformation: The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.
• Half Life: The terminal phase elimination half-life is 0.51 ± 0.31 hours.
• Protein Binding: Plasma protein binding of decitabine is negligible (<1%).
• Clearance: * 125 L/h/m2 [Patients receiving 15 mg/m2 3-hr infusion every 8 hours for 3 days]; * 210 L/h/m2 [20 mg/m2 1-hr infusion daily for 5 days]
• References: Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. [Pubmed] ; Wijermans PW, Ruter B, Baer MR, Slack JL, Hussain SI, Lubbert M: Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2007 Sep 17;. [Pubmed] ; Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. [Pubmed] ; Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. [Pubmed] ; Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. [Pubmed] ; Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. [Pubmed] ; Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [Pubmed]
• External Links: Wikipedia; Drugs.com

Selleck Chemicals - S1200

Research Area

• Description: Ovarian cancer,Myelodysplastic syndromes

Biological Activity

• Description: Decitabine is a potent inhibitor of DNA methylation with IC50 of 438 nM and 4.38 nM in HL-60 and KG1a cells, respectively.
• Targets: DNA methyltransferase (HL-60); DNA methyltransferase (KG1a)
• IC50: 100 ng/mL; 1 ng/mL ^[1]
• In Vitro: Decitabine inhibits cell growth in a dose and time-dependent manner with IC50 of approximately 438 nM and 43.8 nM for 72 hours and 96 hours exposure in HL-60 and KG1a leukemic cells, respectively. ^[1] A recent study shows that Decitabine exhibits high anti-proliferative and pro-apoptotic activity against anaplastic large cell lymphoma (ALCL), and inhibits [^3H]–thymidine uptake in KARPAS-299 cells with EC50 of 0.49 μM. ^[2]
• In Vivo: In a ALK+ KARPAS-299 murine xenograft model, Decitabine at a dose of 2.5 mg/kg causes increased apoptosis and reduced proliferation of tumor cells, and also results in demethylation of tumor suppressor p16INK4A. ^[2]
• Clinical Trials: Decitabine is currently in Phase I clinical trials in patients with Higher-risk MDS and MDS/AML Receiving Allogeneic Stem Cell Transplantation.

Combination Therapy

• Description: Combination of Decitabine (100 ng/mL) and Trichostatin A (TSA) (3 ng/mL), a potent inhibitor of histone deacetylase, shows an additive effect on the DNA synthesis inhibition in both HL-60 and KG1a leukemic cell lines. Combination of Decitabine and TSA leads to greater growth inhibition of HL-60 and KG1a leukemic cells than either agent alone. ^[1] Combination treatment of Decitabine and Dasatinib is currently in Phase I clinical trials in patients with Accelerated or Blastic Phase Chronic Myelogenous Leukemia.

Protocol

• Protocol: Kinase Assay ^[1]
• DNA synthesis assay: The rate of DNA synthesis is measured by the incorporation of radioactive thymidine into DNA. HL-60 and KG1a cells are suspended in 2 mL RPMI medium containing 10% fetal serum in 6-well (35 mm diameter) dishes and incubated with different concentrations of corresponding drugs for 48 hours (drugs are added simultaneously). At 48 hours, 0.5 μCi [^3H] thymidine (6.7 Ci/mmol) is added to each well and incubated for an additional 24 hours. The cells are placed on GF/C glass fiber filters (2.4 cm diameter), washed with cold 0.9% NaCl, 5% cold trichloroacetic acid and ethanol. The filters containing the DNA are then dried, placed in EcoLite scintillation liquid (ICN) and the radioactivity measured using Beckman LS 6000IC scintillation counter. The IC50 is defined as the concentration of drug that inhibits 50% of the DNA synthesis of the leukemic cell lines from the dose–response curve.
• Protocol: Cell Assay ^[1]
• Cell Lines: HL-60 and KG1a
• Concentrations: 0-500 nM
• Incubation Time: 96 hours
• Methods: For the growth inhibition assay, cells in log phase are placed in 5 mL of medium. Different concentrations of Decitabine are added to the medium simultaneously. Cell counts are performed at the indicated times using a model ZM Coulter Counter. The concentration that produces 50% inhibition of growth (IC50) is determined from the growth curves of the drug treated leukemic cell lines.
• Protocol: Animal Study ^[2]
• Animal Models: KARPAS-299 human cells are inoculated subcutaneously into the right and left flanks of the mice.
• Formulation: Decitabine is dissolved in sterile PBS .
• Doses: ≤2.5 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Shaker S, et al. Leuk Res, 2003, 27(5), 437-444.
• References: [2] Hassler MR, et al. Biochimie, 2012, doi.org/10.1016/j.biochi.2012.05.029.

Sigma Aldrich - A3656

Frequently Asked Questions
Live Chat and Frequently Asked Questions are available for this Product.
General description
Decitabine is an epigenetic modifier that inhibits DNA methyltransferase activity which results in DNA demethylation (hypomethylation) and gene activation by remodeling "opening" chromatin. Genes are synergistically reactivated when demethylation is combined with histone hyperacetylation.
Biochem/physiol Actions
5′-Azadeoxycytidine causes DNA demethylation or hemi-demethylation. DNA demethylation can regulate gene expression by "opening" the chromatin structure detectable as increased nuclease sensitivity. This remodeling of chromatin structure allows transcription factors to bind to the promoter regions, assembly of the transcription complex, and gene expression.

Sigma Aldrich - 11390

Other Notes
A very potent cytotoxic agent to tumour cells in vitro at concentrations that do not inhibit macromolecular synthesis1

REFERENCES

• Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. Pubmed
• Wijermans PW, Ruter B, Baer MR, Slack JL, Hussain SI, Lubbert M: Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2007 Sep 17;. Pubmed
• Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. Pubmed
• Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. Pubmed
• Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. Pubmed
• Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. Pubmed
• Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. Pubmed
• Shaker S, et al. Leuk Res, 2003, 27(5), 437-444.
• Hassler MR, et al. Biochimie, 2012, doi.org/10.1016/j.biochi.2012.05.029.