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Identification
NameDecitabine
Accession NumberDB01262
Typesmall molecule
Groupsapproved, 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.

Structure
Thumb
Synonyms
SynonymLanguageCode
4-amino-1-(2-Deoxy-beta-D-erythro-pentofuranosyl)-S-triazin-2(1H)-oneNot AvailableNot Available
5-aza-2'-deoxycytidineNot AvailableNot Available
5-AzadeoxycytidineNot AvailableNot Available
AzadcNot AvailableNot Available
DecitabineNot AvailableNot Available
DezocitidineNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
DacogenNot Available
Brand mixturesNot Available
Categories
CAS number2353-33-5
WeightAverage: 228.2053
Monoisotopic: 228.085854892
Chemical FormulaC8H12N4O4
InChI KeyXAUDJQYHKZQPEU-KVQBGUIXSA-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
IUPAC Name
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
SMILES
NC1=NC(=O)N(C=N1)[C@H]1C[C@H](O)[C@@H](CO)O1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentPyrimidine Nucleosides and Analogues
Alternative parentsPentoses; Triazinones; Aminotriazines; Primary Aromatic Amines; Tetrahydrofurans; Oxolanes; Secondary Alcohols; Polyamines; Ethers; Primary Alcohols
Substituentspentose monosaccharide; amino-1,3,5-triazine; triazinone; triazine; primary aromatic amine; monosaccharide; tetrahydrofuran; oxolane; secondary alcohol; polyamine; ether; primary alcohol; alcohol; organonitrogen compound; primary amine; amine
Classification descriptionThis compound belongs to the pyrimidine nucleosides and analogues. These are compounds comprising a pyrimidine base attached to a sugar.
Pharmacology
IndicationFor 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).
PharmacodynamicsDecitabine 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.
Mechanism of actionDecitabine is believed to exert its antineoplastic effects following its conversion to decitabine triphosphate, where the drug directly incorporates into DNA and inhibits DNA methyltransferase, the enzyme that is responsible for methylating newly synthesized DNA in mammalian cells. This results in hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine that has been incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine. Decitabine is cell cycle specific and acts peripherally in the S phase of the cell cycle. It does not inhibit the progression of cells from the G1 to S phase.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingPlasma protein binding of decitabine is negligible (<1%).
Metabolism

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.

Route of eliminationNot Available
Half lifeThe terminal phase elimination half-life is 0.51 ± 0.31 hours.
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]
ToxicityThere 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9862
Blood Brain Barrier + 0.8787
Caco-2 permeable - 0.8362
P-glycoprotein substrate Non-substrate 0.7192
P-glycoprotein inhibitor I Non-inhibitor 0.9216
P-glycoprotein inhibitor II Non-inhibitor 0.953
Renal organic cation transporter Non-inhibitor 0.8791
CYP450 2C9 substrate Non-substrate 0.8359
CYP450 2D6 substrate Non-substrate 0.8511
CYP450 3A4 substrate Non-substrate 0.5356
CYP450 1A2 substrate Non-inhibitor 0.9276
CYP450 2C9 substrate Non-inhibitor 0.9265
CYP450 2D6 substrate Non-inhibitor 0.9446
CYP450 2C19 substrate Non-inhibitor 0.9379
CYP450 3A4 substrate Non-inhibitor 0.9635
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9629
Ames test Non AMES toxic 0.588
Carcinogenicity Non-carcinogens 0.8109
Biodegradation Not ready biodegradable 0.8957
Rat acute toxicity 1.9436 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9654
hERG inhibition (predictor II) Non-inhibitor 0.8972
Pharmacoeconomics
Manufacturers
  • Eisai inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
Prices
Unit descriptionCostUnit
Dacogen 50 mg vial1706.4USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySparingly solubleNot Available
Predicted Properties
PropertyValueSource
water solubility5.50e+00 g/lALOGPS
logP-2ALOGPS
logP-2.2ChemAxon
logS-1.6ALOGPS
pKa (strongest acidic)13.89ChemAxon
pKa (strongest basic)-0.25ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count7ChemAxon
hydrogen donor count3ChemAxon
polar surface area120.74ChemAxon
rotatable bond count2ChemAxon
refractivity50.68ChemAxon
polarizability21.15ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Julian Paul Henschke, Xiaoheng Zhang, Jianbo Yu, Kun Hu, Lijun Mei, “Synthesis of Decitabine.” U.S. Patent US20100087637, issued April 08, 2010.

US20100087637
General Reference
  1. 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
  2. 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
  3. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. Pubmed
  4. Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. Pubmed
  5. 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
  6. 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
  7. 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
ResourceLink
KEGG DrugD03665
PubChem Compound451668
PubChem Substance46505657
ChemSpider397844
ChEBI50131
ChEMBLCHEMBL1201129
Therapeutic Targets DatabaseDAP000641
PharmGKBPA164749631
Drugs.comhttp://www.drugs.com/cdi/decitabine.html
WikipediaDecitabine
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(100 KB)
MSDSNot Available
Interactions
Drug InteractionsSearched, but no interactions found.
Food InteractionsNot Available

Targets

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: other/unknown

Components

Name UniProt ID Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. 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
  4. Claus R, Ruter B, Lubbert M: Targets of epigenetic therapy – Gene reactivation as a novel approach in MDS treatment. Cancer Treat Rev. 2007 Sep 27. doi:10.1016/j.ctrv.2007.07.009
  5. Atallah E, Kantarjian H, Garcia-Manero G: The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin Pharmacother. 2007 Jan;8(1):65-73. Pubmed
  6. 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
  7. 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
  8. 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

2. DNA (cytosine-5)-methyltransferase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA (cytosine-5)-methyltransferase 1 P26358 Details

References:

  1. Ando T, Nishimura M, Oka Y: Decitabine (5-Aza-2’-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. Leukemia. 2000 Nov;14(11):1915-20. Pubmed
  2. Karpf AR, Moore BC, Ririe TO, Jones DA: Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2’-deoxycytidine. Mol Pharmacol. 2001 Apr;59(4):751-7. Pubmed
  3. Csankovszki G, Nagy A, Jaenisch R: Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol. 2001 May 14;153(4):773-84. Pubmed
  4. Takebayashi S, Nakao M, Fujita N, Sado T, Tanaka M, Taguchi H, Okumura K: 5-Aza-2’-deoxycytidine induces histone hyperacetylation of mouse centromeric heterochromatin by a mechanism independent of DNA demethylation. Biochem Biophys Res Commun. 2001 Nov 9;288(4):921-6. Pubmed
  5. Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J: Effects of 5-aza-2’-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003 Dec 1;102(12):3865-70. Epub 2003 Aug 7. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. Pubmed
  8. Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. Pubmed
  9. 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
  10. 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
  11. 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

Enzymes

1. Deoxycytidine kinase

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Deoxycytidine kinase P27707 Details

References:

  1. Schwarzenberg J, Radu CG, Benz M, Fueger B, Tran AQ, Phelps ME, Witte ON, Satyamurthy N, Czernin J, Schiepers C: Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):711-21. Epub 2010 Dec 3. Pubmed

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Drug created on May 16, 2007 11:38 / Updated on September 16, 2013 17:13