Banner
targets (3) enzymes (1)
for drugs
Identification
Name Azacitidine
Accession Number DB00928 (APRD00809)
Type small molecule
Groups approved
Description

A pyrimidine nucleoside analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
5 AZC
Azacitidina [INN-Spanish]
Azacitidinum [INN-Latin]
Azacytidine
Salts Not Available
Brand names
Name Company
Ladakamycin
Mylosar
Vidaza
Brand mixtures Not Available
Categories
  • Enzyme Inhibitors
  • Antimetabolites, Antineoplastic
CAS number 320-67-2
Weight Average: 244.2047
Monoisotopic: 244.080769514
Chemical Formula C8H12N4O5
InChI Key InChIKey=NMUSYJAQQFHJEW-KVTDHHQDSA-N
InChI
InChI=1S/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
Plain Text
IUPAC Name
4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
SMILES
NC1=NC(=O)N(C=N1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbohydrates
Substructures
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Aliphatic and Aryl Amines
  • Ethers
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Triazines
  • Furans
  • Cyanamides
  • Carbohydrates
Pharmacology
Indication For treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (now classified as acute myelogenous leukemia with multilineage dysplasia), and chronic myelomonocytic leukemia.
Pharmacodynamics Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. Upon uptake into cells, azacitidine is phosphorylated to 5-azacytidine monophosphate by uridine-cytidine kinase, then to diphosphate by pyrimidine monophosphate kinases and triphosphate by diphosphate kinases. 5-Azacitidine triphosphate is incorporated into RNA, leading to the disruption of nuclear and cytoplasmic RNA metabolism and inhibition of protein synthesis. 5-Azacytidine diphosphate is reduced to 5-aza-deoxycytidine diphosphate by ribonucleotide reductase. The resultant metabolite is phosphorylated to 5-azadeoxycitidine triphosphate by nucleoside diphosphate kinases. 5-azadeoxycitidine triphosphate is then incoporated into DNA, leading to inhibition of DNA synthesis. Azacitidine is most toxic during the S-phase of the cell cycle.
Mechanism of action Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside used in DNA and RNA. Azacitidine is thought to induce antineoplastic activity via two mechanisms; inhibition of DNA methyltransferase at low doses, causing hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA at high doses, resulting in cell death. As azacitidine is a ribonucleoside, it incoporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the dissembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein. Its incorporation into DNA leads to a covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequent cytotoxicity.
Absorption Azacitidine is rapidly absorbed after subcutaneous administration. The bioavailability of subcutaneous azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve.
Volume of distribution
  • 76 ± 26 L
Protein binding Not Available
Metabolism An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. The potential of azacitidine to inhibit cytochrome P450 (CYP) enzymes is not known.
Route of elimination Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over three days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%.
Half life Mean elimination half-life is approximately 4 hours.
Clearance
  • 167 +/- 49 L/h
Toxicity One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2, almost 4 times the recommended starting dose.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Celgene corp
Packagers
Dosage forms
Form Route Strength
Injection, powder, for solution Subcutaneous
Prices
Unit description Cost Unit
Vidaza 100 mg vial 588.23 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 229 °C PhysProp
water solubility 8.9E+004 mg/L Not Available
logP -3.5 Not Available
Predicted Properties
Property Value Source
water solubility 1.21e+01 g/l ALOGPS
logP -2.5 ALOGPS
logP -3.1 ChemAxon
logS -1.3 ALOGPS
pKa (strongest acidic) 12.55 ChemAxon
pKa (strongest basic) -0.38 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 140.97 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 52.19 ChemAxon
polarizability 21.5 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Cihak A: Biological effects of 5-azacytidine in eukaryotes. Oncology. 1974;30(5):405-22. Pubmed
  2. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  3. Leone G, Voso MT, Teofili L, Lubbert M: Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003 Oct;109(1):89-102. Pubmed
  4. Ghoshal K, Bai S: DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 2007 Jun;43(6):395-422. Pubmed
  5. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. Pubmed
  6. Silverman LR: Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001;6 Suppl 5:8-14. Pubmed
  7. Issa JP, Kantarjian H: Azacitidine. Nat Rev Drug Discov. 2005 May;Suppl:S6-7. Pubmed
  8. O’Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. Pubmed
  9. Siddiqui MA, Scott LJ: Azacitidine: in myelodysplastic syndromes. Drugs. 2005;65(13):1781-9; discussion 1790-1. Pubmed
  10. Abdulhaq H, Rossetti JM: The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opin Investig Drugs. 2007 Dec;16(12):1967-75. Pubmed
  11. Keating GM: Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Drugs. 2009;69(17):2501-18. doi: 10.2165/11202840-000000000-00000. Pubmed
  12. Sullivan M, Hahn K, Kolesar JM: Azacitidine: a novel agent for myelodysplastic syndromes. Am J Health Syst Pharm. 2005 Aug 1;62(15):1567-73. Pubmed
  13. Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. Pubmed
External Links
Resource Link
KEGG Drug D03021 Link_out
KEGG Compound C11262 Link_out
PubChem Compound 9444 Link_out
PubChem Substance 46509032 Link_out
ChemSpider 9072 Link_out
ChEBI 2038 Link_out
ChEMBL 2038 Link_out
Therapeutic Targets Database DAP000640 Link_out
PharmGKB PA451996 Link_out
RxList http://www.rxlist.com/cgi/generic3/vidaza.htm Link_out
Drugs.com http://www.drugs.com/cdi/azacitidine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Azacitidine Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (194 KB)
MSDS show (68.8 KB)
Interactions
Drug Interactions
Drug Interaction
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available
Targets

1. DNA (cytosine-5)-methyltransferase 1

Pharmacological action: yes
Actions: inhibitor

Methylates CpG residues. Preferentially methylates hemimethylated DNA. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2

Organism class: human
UniProt ID: P26358 Link_out
Gene: DNMT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  3. Cataldo VD, Cortes J, Quintas-Cardama A: Azacitidine for the treatment of myelodysplastic syndrome. Expert Rev Anticancer Ther. 2009 Jul;9(7):875-84. Pubmed
  4. Leone G, Voso MT, Teofili L, Lubbert M: Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003 Oct;109(1):89-102. Pubmed
  5. Ghoshal K, Bai S: DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 2007 Jun;43(6):395-422. Pubmed
  6. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. Pubmed
  7. Fenaux P: Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S36-44. Pubmed
  8. Silverman LR: Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001;6 Suppl 5:8-14. Pubmed
  9. O’Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. Pubmed
  10. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. Pubmed
  11. Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. Pubmed

2. RNA

Pharmacological action: yes
Actions: other

References:
  1. Muller A, Florek M: 5-Azacytidine/Azacitidine. Recent Results Cancer Res. 2010;184:159-70. Pubmed
  2. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  3. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. Pubmed
  4. Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. Pubmed
  5. Cihak A, Vesely J, Skoda J: Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335-54. Pubmed
  6. Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. Pubmed

3. DNA

Pharmacological action: yes
Actions: other

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

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. Allen A: Epigenetic alterations and cancer: New targets for therapy. IDrugs. 2007 Oct;10(10):709-12. Pubmed
  4. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  5. O’Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. Pubmed
  6. Muller A, Florek M: 5-Azacytidine/Azacitidine. Recent Results Cancer Res. 2010;184:159-70. Pubmed
  7. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. Pubmed
  8. Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. Pubmed
  9. Cihak A, Vesely J, Skoda J: Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335-54. Pubmed
  10. Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. Pubmed
Enzymes

1. Cytidine deaminase

Actions: substrate

This enzyme scavenge exogenous and endogenous cytidine and 2'-deoxycytidine for UMP synthesis

UniProt ID: P32320 Link_out
Gene: CDA
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S: A pilot pharmacokinetic study of oral azacitidine. Leukemia. 2008 Sep;22(9):1680-4. Epub 2008 Jun 12. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19