T3DB: Flucytosine

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (2)XML

Targets (2)

Record Information

Version

2.0

Creation Date

2009-07-21 20:28:21 UTC

Update Date

2014-12-24 20:25:54 UTC

Accession Number

T3D2983

Identification

Common Name

Flucytosine

Class

Small Molecule

Description

Flucytosine is only found in individuals that have used or taken this drug. It is a fluorinated cytosine analog that is used as an antifungal agent. [PubChem]Although 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.

Compound Type

Amine
Antifungal Agent
Antimetabolite
Drug
Metabolite
Organic Compound
Organofluoride
Synthetic Compound

Chemical Structure

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

Synonym
5-FC
5-Fluorocystosine
5-Fluorocytosin
5-Fluorocytosine
5-Flurocytosine
Ancobon
Ancotil
Flucytosin
Fluocytosine
Fluorcytosine
Flusine

Chemical Formula

C₄H₄FN₃O

Average Molecular Mass

129.093 g/mol

Monoisotopic Mass

129.034 g/mol

CAS Registry Number

2022-85-7

IUPAC Name

6-amino-5-fluoro-1,2-dihydropyrimidin-2-one

Traditional Name

flucytosine

SMILES

OC1=NC=C(F)C(=N)N1

InChI Identifier

InChI=1S/C4H4FN3O/c5-2-1-7-4(9)8-3(2)6/h1H,(H3,6,7,8,9)

InChI Key

InChIKey=XRECTZIEBJDKEO-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazines

Sub Class

Pyrimidines and pyrimidine derivatives

Direct Parent

Halopyrimidines

Alternative Parents

Substituents

Aminopyrimidine
Halopyrimidine
Pyrimidone
Aryl fluoride
Aryl halide
Hydropyrimidine
Heteroaromatic compound
Azacycle
Amine
Primary amine
Organooxygen compound
Organonitrogen compound
Organofluoride
Organohalogen compound
Hydrocarbon derivative
Organic oxide
Organopnictogen compound
Organic oxygen compound
Organic nitrogen compound
Aromatic heteromonocyclic compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

organofluorine compound (CHEBI:5100 )
aminopyrimidine (CHEBI:5100 )
pyrimidone (CHEBI:5100 )
nucleoside analogue (CHEBI:5100 )
pyrimidine antifungal drug (CHEBI:5100 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

antifungal agent

Biological Roles

antifungal agent

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	296°C
Boiling Point	Not Available
Solubility	1.5E+004 mg/L (at 25°C)
LogP	-1.1

Predicted Properties

Property	Value	Source
Water Solubility	1.92 g/L	ALOGPS
logP	-0.24	ALOGPS
logP	-0.95	ChemAxon
logS	-1.8	ALOGPS
pKa (Strongest Acidic)	8.16	ChemAxon
pKa (Strongest Basic)	1.06	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	67.48 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	38.22 m³·mol⁻¹	ChemAxon
Polarizability	9.97 Å³	ChemAxon
Number of Rings	1	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-004i-5900000000-62cd06162d248f459f77	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-002r-9400000000-acd1b588a4052f6fc2dd	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-002r-9400000000-a4e7dd3c4c886861c0ea	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-000i-9200000000-b3fb9cad9c2b375b08c6	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-000i-9100000000-11fb61e55faa71878d87	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-000i-9000000000-13935b6ab4a3d8adaa08	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-000i-9000000000-cd981efe159dd44555f4	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-001i-0900000000-a228aa7f5ecaf516455f	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-001i-0900000000-ec5b7f7d9f3c75649dc2	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-03e9-0900000000-15df2a7b685c4dd4ca17	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-001i-0900000000-7110f8accb80c700a2a5	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-001i-0900000000-89290e0501d587938afb	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-001i-0900000000-7248b6df062077397b61	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-001i-1900000000-df83e87e1bcbc8311be6	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-01q9-3900000000-42649a5ceee8a4619fc3	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-08gr-9800000000-8cb7a586d34dd7913561	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 0V, Positive	splash10-001i-0900000000-973610269bb11b2539b9	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-001i-0900000000-f98fd5ea350e99bcbb13	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 0V, Positive	splash10-001i-0900000000-f0b5eaeae6c5f2a922c3	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-0bti-9300000000-c7808ed54724dbe0b4db	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-001i-0900000000-3daf46ab201d0847e716	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-001i-4900000000-08676c044da012e58509	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0007-9000000000-fc78e7fb18ada3e97d98	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-004i-2900000000-d0b2503a7f5865ac1efd	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-00nu-9100000000-ee11917ba44963a8210b	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9000000000-e5c5889e9b5cd0c8cae9	2016-08-03	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum

Toxicity Profile

Route of Exposure

Rapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%.

Mechanism of Toxicity

Although 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.

Metabolism

Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite. Route of Elimination: Flucytosine 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 Life: 2.4 to 4.8 hours.

Toxicity Values

LD50: 15 gm/kg (Oral, Rat) (1)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For 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).

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancobon is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted. Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage. (5)

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

Not Available

UniProt ID

Not Available

OMIM ID

ChEBI ID

5100

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Flucytosine

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Flucytosine

References

Synthesis Reference

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

MSDS

Link

General References

Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Bertout S, Dunyach C, Drakulovski P, Reynes J, Mallie M: Comparison of the Sensititre YeastOne(R) dilution method with the Clinical Laboratory Standards Institute (CLSI) M27-A3 microbroth dilution reference method for determining MIC of eight antifungal agents on 102 yeast strains. Pathol Biol (Paris). 2011 Feb;59(1):48-51. doi: 10.1016/j.patbio.2010.07.020. Epub 2010 Sep 16. [20843616 ]
Kaouech E, Kallel K, Belhadj S, Anane S, Ben Chaabane T, Ben Fadhl K, Khedher A, Meddeb B, Ben Lakhal S, Chaker E: [Twenty-two cases of neuromeningeal cryptococcosis in Tunisia]. Med Mal Infect. 2009 Dec;39(12):914-9. doi: 10.1016/j.medmal.2009.02.004. Epub 2009 Apr 8. [19359114 ]
Park BJ, Park JC, Taguchi H, Fukushima K, Hyon SH, Takatori K: Antifungal susceptibility of epigallocatechin 3-O-gallate (EGCg) on clinical isolates of pathogenic yeasts. Biochem Biophys Res Commun. 2006 Aug 25;347(2):401-5. Epub 2006 Jun 15. [16831406 ]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

1. DNA

General Function:: Used for biological information storage.
Specific Function:: DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:: 2.15 x 10¹² Da

References

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. [3167042 ]
Waldorf AR, Polak A: Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983 Jan;23(1):79-85. [6338821 ]
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. [8441637 ]

Target Details

2. DNA (cytosine-5)-methyltransferase 1

General Function:: Zinc ion binding
Specific Function:: Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. 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. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.
Gene Name:: DNMT1
Uniprot ID:: P26358
Molecular Weight:: 183163.635 Da

References

Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]

Flucytosine (T3D2983)

Structure for T3D2983: Flucytosine

Targets

References

References