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Fluorouracil (T3D4776)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (5)XML
Targets (5)
Record Information
Version2.0
Creation Date2014-09-11 05:16:06 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4776
Identification
Common NameFluorouracil
ClassSmall Molecule
DescriptionA pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid.
Compound Type
  • Amide
  • Antimetabolite
  • Antimetabolite, Antineoplastic
  • Drug
  • Immunosuppressive Agent
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
5-Fluoracil
5-Fluoropyrimidine-2,4-dione
5-Fluorouracil
5-Fluracil
5-FU
Adrucil
Carac
Carzonal
Efudex
Efudix
Efurix
Fluoro Uracil
Fluoroplex
Fluorouracilo
Fluorouracilum
Fluouracil
Ftoruracil
FU
Chemical FormulaC4H3FN2O2
Average Molecular Mass130.077 g/mol
Monoisotopic Mass130.018 g/mol
CAS Registry Number51-21-8
IUPAC Name5-fluoro-1,2,3,4-tetrahydropyrimidine-2,4-dione
Traditional Namefluorouracil
SMILESOC1=NC=C(F)C(O)=N1
InChI IdentifierInChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
InChI KeyInChIKey=GHASVSINZRGABV-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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentHalopyrimidines
Alternative Parents
Substituents
  • Hydroxypyrimidine
  • Halopyrimidine
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Azacycle
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Kidney
  • Liver
Pathways
NameSMPDB LinkKEGG Link
Capecitabine PathwayNot AvailableNot Available
Fluorouracil PathwayNot AvailableNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point282-283°C
Boiling PointNot Available
Solubility1.11E+004 mg/L (at 22°C)
LogP-0.89
Predicted Properties
PropertyValueSource
Water Solubility5.86 g/LALOGPS
logP-0.58ALOGPS
logP-0.66ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)7.18ChemAxon
pKa (Strongest Basic)-8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.2 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity26.17 m³·mol⁻¹ChemAxon
Polarizability9.46 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-001i-9800000000-a3301f9fea9145d07480View in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0900000000-76691bd3cba2765d3687View in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0900000000-d801d8209e9a5aa4830bView in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-0002-0900000000-7521695ae4a96b4a5a98View in MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-001i-9800000000-a3301f9fea9145d07480View in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0900000000-76691bd3cba2765d3687View in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0900000000-d801d8209e9a5aa4830bView in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-0002-0900000000-7521695ae4a96b4a5a98View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-001i-9600000000-8c2b278c2716f3e6b27cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-c639ed1b5365f368b59cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-1a7a70df49a360e1458cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-d89f2d944fe1cac39f55View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-50b33770c08680863cf6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-cd5bef421a05073cb1f3View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-3900000000-ec9c9e1dfc9a16f625a2View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-df98a4532ca49a0a0436View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-50b33770c08680863cf6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-50b33770c08680863cf6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-df98a4532ca49a0a0436View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-004i-0900000000-b117f5fa58c8f98b5c15View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-0a4i-9000000000-f3e71a41b6d4417d33fdView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-001i-9200000000-29362607b7c48b82973cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-001i-0900000000-693d492f316b0c7d5ed5View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-001i-1900000000-0c0ee9469bf49688c5d2View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-001i-1900000000-0cecca0d265e958e19d7View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03e9-1900000000-46f20f71dbc96630cee7View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-1900000000-4330f38956afe6c47636View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-2900000000-f935071622b89177697bView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-1900000000-3fa9b91447db7dc7ba77View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01q9-9800000000-32bf878787078ce9d817View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-03di-9000000000-3ef559051a5b99c94b29View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-4900000000-82764fbca3290816328dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000f-9100000000-2da5eb3c925c027b5022View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9000000000-1cf432837297c55833a5View in MoNA
MSMass Spectrum (Electron Ionization)splash10-001i-9400000000-b8247c8f5c45b12efaa6View in MoNA
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
Toxicity Profile
Route of Exposure28-100%
Mechanism of ToxicityThe precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5дус10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.
MetabolismHepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and alpha-fluoro-beta-alanine) which are inactive. Route of Elimination: Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. Half Life: 10-20 minutes
Toxicity ValuesLD50=230mg/kg (orally in mice)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (3)
Uses/SourcesFor the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00544
HMDB IDHMDB14684
PubChem Compound ID3385
ChEMBL IDCHEMBL185
ChemSpider ID3268
KEGG IDC07649
UniProt IDNot Available
OMIM ID
ChEBI ID46345
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDURF
ACToR IDNot Available
Wikipedia LinkFluorouracil
References
Synthesis Reference

Leroy B. Townsend, Robert A. Earl, Steven J. Manning, “Method of synthesizing 1-(tetrahydro-2-furanyl)-5-fluorouracil.” U.S. Patent US3960864, issued October, 1969.

MSDSLink
General References
  1. Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. [12724731 ]
  2. Petty RD, Cassidy J: Novel fluoropyrimidines: improving the efficacy and tolerability of cytotoxic therapy. Curr Cancer Drug Targets. 2004 Mar;4(2):191-204. [15032669 ]
  3. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Thymidylate synthase
General Function:
Thymidylate synthase activity
Specific Function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:
TYMS
Uniprot ID:
P04818
Molecular Weight:
35715.65 Da
References
  1. Formentini A, Sander S, Denzer S, Straeter J, Henne-Bruns D, Kornmann M: Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker? Int J Colorectal Dis. 2007 Jan;22(1):49-55. Epub 2006 Mar 15. [16538493 ]
  2. Huang CL, Yokomise H, Fukushima M, Kinoshita M: Tailor-made chemotherapy for non-small cell lung cancer patients. Future Oncol. 2006 Apr;2(2):289-99. [16563096 ]
  3. Fernandez-Contreras ME, Sanchez-Prudencio S, Sanchez-Hernandez JJ, Garcia de Paredes ML, Gisbert JP, Roda-Navarro P, Gamallo C: Thymidylate synthase expression pattern, expression level and single nucleotide polymorphism are predictors for disease-free survival in patients of colorectal cancer treated with 5-fluorouracil. Int J Oncol. 2006 May;28(5):1303-10. [16596248 ]
  4. Garcia V, Garcia JM, Pena C, Silva J, Dominguez G, Hurtado A, Alonso I, Rodriguez R, Provencio M, Bonilla F: Thymidylate synthase messenger RNA expression in plasma from patients with colon cancer: prognostic potential. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2095-100. [16609021 ]
  5. Ploylearmsaeng SA, Fuhr U, Jetter A: How may anticancer chemotherapy with fluorouracil be individualised? Clin Pharmacokinet. 2006;45(6):567-92. [16719540 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  7. Rustum YM: Thymidylate synthase: a critical target in cancer therapy? Front Biosci. 2004 Sep 1;9:2467-73. [15353299 ]
2. 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
  1. Wyatt MD, Wilson DM 3rd: Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci. 2009 Mar;66(5):788-99. doi: 10.1007/s00018-008-8557-5. [18979208 ]
  2. Ghoshal K, Jacob ST: An alternative molecular mechanism of action of 5-fluorouracil, a potent anticancer drug. Biochem Pharmacol. 1997 Jun 1;53(11):1569-75. [9264308 ]
  3. Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. [12724731 ]
  4. Petty RD, Cassidy J: Novel fluoropyrimidines: improving the efficacy and tolerability of cytotoxic therapy. Curr Cancer Drug Targets. 2004 Mar;4(2):191-204. [15032669 ]
3. RNA
References
  1. Wyatt MD, Wilson DM 3rd: Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci. 2009 Mar;66(5):788-99. doi: 10.1007/s00018-008-8557-5. [18979208 ]
  2. Ghoshal K, Jacob ST: An alternative molecular mechanism of action of 5-fluorouracil, a potent anticancer drug. Biochem Pharmacol. 1997 Jun 1;53(11):1569-75. [9264308 ]
  3. Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. [12724731 ]
  4. Petty RD, Cassidy J: Novel fluoropyrimidines: improving the efficacy and tolerability of cytotoxic therapy. Curr Cancer Drug Targets. 2004 Mar;4(2):191-204. [15032669 ]
Target Details
4. ATPase family AAA domain-containing protein 5
General Function:
Atp binding
Specific Function:
Involved in DNA damage response. Involved in a RAD9A-related damage checkpoint, a pathway that is important in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis. Modulates the RAD9A interaction with BCL2 and thereby induces DNA damages-induced apoptosis.
Gene Name:
ATAD5
Uniprot ID:
Q96QE3
Molecular Weight:
207568.185 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.76 uMTox21_ELG1_LUC_AgonistTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
5. Bile acid receptor
General Function:
Zinc ion binding
Specific Function:
Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.
Gene Name:
NR1H4
Uniprot ID:
Q96RI1
Molecular Weight:
55913.915 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC505.7 uMOT_SRC1_SRC1FXR_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]