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Identification
NameFlucytosine
Accession NumberDB01099  (APRD00299)
Typesmall molecule
Groupsapproved
Description

A fluorinated cytosine analog that is used as an antifungal agent. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
5-FCNot AvailableNot Available
5-FluorocystosineNot AvailableNot Available
5-FluorocytosinNot AvailableNot Available
5-FluorocytosineNot AvailableNot Available
5-FlurocytosineNot AvailableNot Available
FlucytosinNot AvailableNot Available
FluocytosineNot AvailableNot Available
FluorcytosineNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AncobonNot Available
AncotilNot Available
Brand mixturesNot Available
Categories
CAS number2022-85-7
WeightAverage: 129.0925
Monoisotopic: 129.03383997
Chemical FormulaC4H4FN3O
InChI KeyInChIKey=XRECTZIEBJDKEO-UHFFFAOYSA-N
InChI
InChI=1S/C4H4FN3O/c5-2-1-7-4(9)8-3(2)6/h1H,(H3,6,7,8,9)
IUPAC Name
6-amino-5-fluoro-1,2-dihydropyrimidin-2-one
SMILES
NC1=C(F)C=NC(=O)N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassDiazines
SubclassPyrimidines and Pyrimidine Derivatives
Direct parentHalopyrimidines
Alternative parentsPyrimidones; Aminopyrimidines and Derivatives; Hydropyrimidines; Primary Aromatic Amines; Aryl Fluorides; Polyamines; Organofluorides
Substituentsaryl fluoride; primary aromatic amine; aryl halide; hydropyrimidine; polyamine; organofluoride; amine; organohalogen; primary amine; organonitrogen compound
Classification descriptionThis compound belongs to the halopyrimidines. These are aromatic compounds containing an halogen atom linked to a pyrimidine ring.
Pharmacology
IndicationFor the treatment (in combination with amphotericin B) of serious infections caused by susceptible strains of Candida (septicemia, endocarditis and urinary system infections) and/or Cryptococcus (meningitis and pulmonary infections).
PharmacodynamicsFlucytosine is an antimetabolite that acts as an antifungal agent with in vitro and in vivo activity against Candida and Cryptococcus. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported.
Mechanism of actionAlthough the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.
AbsorptionRapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%.
Volume of distributionNot Available
Protein binding28-31%
Metabolism

Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite.

Route of eliminationFlucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. A small portion of the dose is excreted in the feces.
Half life2.4 to 4.8 hours.
ClearanceNot Available
ToxicityOral, rat: LD50 = >15 gm/kg.
Affected organisms
  • Yeast and other fungi
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9734
Blood Brain Barrier + 0.9653
Caco-2 permeable - 0.606
P-glycoprotein substrate Non-substrate 0.8098
P-glycoprotein inhibitor I Non-inhibitor 0.9304
P-glycoprotein inhibitor II Non-inhibitor 0.9945
Renal organic cation transporter Non-inhibitor 0.8989
CYP450 2C9 substrate Non-substrate 0.8239
CYP450 2D6 substrate Non-substrate 0.8854
CYP450 3A4 substrate Non-substrate 0.7224
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9629
CYP450 2D6 substrate Non-inhibitor 0.9669
CYP450 2C19 substrate Non-inhibitor 0.918
CYP450 3A4 substrate Non-inhibitor 0.9831
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9703
Ames test Non AMES toxic 0.692
Carcinogenicity Non-carcinogens 0.9287
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 1.9498 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9624
hERG inhibition (predictor II) Non-inhibitor 0.9071
Pharmacoeconomics
Manufacturers
  • Valeant pharmaceuticals international
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
SolutionIntravenous
Prices
Unit descriptionCostUnit
Ancobon 500 mg capsule45.54USDcapsule
Ancobon 250 mg capsule23.09USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point296 °CPhysProp
water solubility1.5E+004 mg/L (at 25 °C)MERCK INDEX (1996)
logP-1.1Not Available
pKa3.26BUDAVARI,S ET AL. (1996)
Predicted Properties
PropertyValueSource
water solubility1.92e+00 g/lALOGPS
logP-0.24ALOGPS
logP-0.95ChemAxon
logS-1.8ALOGPS
pKa (strongest acidic)8.16ChemAxon
pKa (strongest basic)1.06ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count2ChemAxon
polar surface area67.48ChemAxon
rotatable bond count0ChemAxon
refractivity38.22ChemAxon
polarizability9.97ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Bernd Baasner, Erich Klauke, “Process for the preparation of 5-fluorocytosine.” U.S. Patent US4703121, issued September, 1961.

US4703121
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00323
PubChem Compound3366
PubChem Substance46504735
ChemSpider3249
BindingDB50241247
ChEBI5100
ChEMBLCHEMBL1463
Therapeutic Targets DatabaseDAP001542
PharmGKBPA449654
RxListhttp://www.rxlist.com/cgi/generic3/flucytosine.htm
Drugs.comhttp://www.drugs.com/cdi/flucytosine.html
WikipediaFlucytosine
ATC CodesD01AE21J02AX01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(128 KB)
MSDSshow(57.3 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: cross-linking/alkylation

Components

Name UniProt ID Details

References:

  1. Osterman DG, DePillis GD, Wu JC, Matsuda A, Santi DV: 5-Fluorocytosine in DNA is a mechanism-based inhibitor of HhaI methylase. Biochemistry. 1988 Jul 12;27(14):5204-10. Pubmed
  2. Waldorf AR, Polak A: Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983 Jan;23(1):79-85. Pubmed
  3. Wyszynski MW, Gabbara S, Kubareva EA, Romanova EA, Oretskaya TS, Gromova ES, Shabarova ZA, Bhagwat AS: The cysteine conserved among DNA cytosine methylases is required for methyl transfer, but not for specific DNA binding. Nucleic Acids Res. 1993 Jan 25;21(2):295-301. Pubmed

2. DNA (cytosine-5)-methyltransferase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
DNA (cytosine-5)-methyltransferase 1 P26358 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. Shieh FK, Reich NO: AdoMet-dependent Methyl-transfer: Glu(119) Is Essential for DNA C5-Cytosine Methyltransferase M.HhaI. J Mol Biol. 2007 Aug 19;. Pubmed
  4. Wyszynski MW, Gabbara S, Kubareva EA, Romanova EA, Oretskaya TS, Gromova ES, Shabarova ZA, Bhagwat AS: The cysteine conserved among DNA cytosine methylases is required for methyl transfer, but not for specific DNA binding. Nucleic Acids Res. 1993 Jan 25;21(2):295-301. Pubmed

3. Thymidylate synthase

Kind: protein

Organism: Yeast

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Thymidylate synthase P12461 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. Fox BA, Belperron AA, Bzik DJ: Stable transformation of Toxoplasma gondii based on a pyrimethamine resistant trifunctional dihydrofolate reductase-cytosine deaminase-thymidylate synthase gene that confers sensitivity to 5-fluorocytosine. Mol Biochem Parasitol. 1999 Jan 5;98(1):93-103. Pubmed
  4. Rehemtulla A, Hamstra DA, Kievit E, Davis MA, Ng EY, Dornfeld K, Lawrence TS: Extracellular expression of cytosine deaminase results in increased 5-FU production for enhanced enzyme/prodrug therapy. Anticancer Res. 2004 May-Jun;24(3a):1393-9. Pubmed
  5. Wang ZH, Samuels S, Gama Sosa MA, Kolodny EH: 5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon. J Neurooncol. 1998 Feb;36(3):219-29. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13