T3DB: Fluorouracil

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Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (5)XML

Targets (5)

Record Information

Version

2.0

Creation Date

2014-09-11 05:16:06 UTC

Update Date

2014-12-24 20:26:57 UTC

Accession Number

T3D4776

Identification

Common Name

Fluorouracil

Class

Small Molecule

Description

A 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

MOL SDF PDB SMILES InChI

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 Formula

C₄H₃FN₂O₂

Average Molecular Mass

130.077 g/mol

Monoisotopic Mass

130.018 g/mol

CAS Registry Number

51-21-8

IUPAC Name

5-fluoro-1,2,3,4-tetrahydropyrimidine-2,4-dione

Traditional Name

fluorouracil

SMILES

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

InChI Identifier

InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)

InChI Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazines

Sub Class

Pyrimidines and pyrimidine derivatives

Direct Parent

Halopyrimidines

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 Framework

Aromatic heteromonocyclic compounds

External Descriptors

organofluorine compound (CHEBI:46345 )
nucleobase analogue (CHEBI:46345 )
a uracil analogue (CPD0-1327 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Kidney
Liver

Pathways

Name	SMPDB Link	KEGG Link
Capecitabine Pathway	Not Available	Not Available
Fluorouracil Pathway	Not Available	Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	282-283°C
Boiling Point	Not Available
Solubility	1.11E+004 mg/L (at 22°C)
LogP	-0.89

Predicted Properties

Property	Value	Source
Water Solubility	5.86 g/L	ALOGPS
logP	-0.58	ALOGPS
logP	-0.66	ChemAxon
logS	-1.4	ALOGPS
pKa (Strongest Acidic)	7.18	ChemAxon
pKa (Strongest Basic)	-8	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	58.2 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	26.17 m³·mol⁻¹	ChemAxon
Polarizability	9.46 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	View
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-001i-9800000000-a3301f9fea9145d07480	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-001i-0900000000-76691bd3cba2765d3687	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-001i-0900000000-d801d8209e9a5aa4830b	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-0002-0900000000-7521695ae4a96b4a5a98	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-001i-9800000000-a3301f9fea9145d07480	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-001i-0900000000-76691bd3cba2765d3687	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-001i-0900000000-d801d8209e9a5aa4830b	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-0002-0900000000-7521695ae4a96b4a5a98	JSpectraViewer \| MoNA
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-001i-9600000000-8c2b278c2716f3e6b27c	JSpectraViewer
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	JSpectraViewer
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-c639ed1b5365f368b59c	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-1a7a70df49a360e1458c	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-d89f2d944fe1cac39f55	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-50b33770c08680863cf6	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-cd5bef421a05073cb1f3	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-3900000000-ec9c9e1dfc9a16f625a2	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-df98a4532ca49a0a0436	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-50b33770c08680863cf6	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-50b33770c08680863cf6	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-df98a4532ca49a0a0436	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-b117f5fa58c8f98b5c15	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-0a4i-9000000000-f3e71a41b6d4417d33fd	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 30V, Negative	splash10-004i-0900000000-1a7a70df49a360e1458c	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 45V, Negative	splash10-004i-0900000000-d89f2d944fe1cac39f55	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 30V, Negative	splash10-004i-0900000000-50b33770c08680863cf6	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 75V, Negative	splash10-004i-0900000000-cd5bef421a05073cb1f3	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 90V, Negative	splash10-0a4i-9000000000-f3e71a41b6d4417d33fd	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 75V, Negative	splash10-004i-0900000000-b117f5fa58c8f98b5c15	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 90V, Negative	splash10-004i-3900000000-ec9c9e1dfc9a16f625a2	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 60V, Negative	splash10-004i-0900000000-df98a4532ca49a0a0436	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-9200000000-29362607b7c48b82973c	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-693d492f316b0c7d5ed5	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-1900000000-0c0ee9469bf49688c5d2	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-1900000000-0cecca0d265e958e19d7	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-03e9-1900000000-46f20f71dbc96630cee7	JSpectraViewer \| MoNA
MS	Mass Spectrum (Electron Ionization)	splash10-001i-9400000000-b8247c8f5c45b12efaa6	JSpectraViewer \| MoNA
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer

Toxicity Profile

Route of Exposure

28-100%

Mechanism of Toxicity

The 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.

Metabolism

Hepatic. 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 Values

LD₅₀=230mg/kg (orally in mice)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

3, not classifiable as to its carcinogenicity to humans. (3)

Uses/Sources

For 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 Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

46345

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

URF

ACToR ID

Not Available

Wikipedia Link

Fluorouracil

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.

MSDS

Link

General References

Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. [12724731 ]
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 ]
International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not 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

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 ]
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 ]
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 ]
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 ]
Ploylearmsaeng SA, Fuhr U, Jetter A: How may anticancer chemotherapy with fluorouracil be individualised? Clin Pharmacokinet. 2006;45(6):567-92. [16719540 ]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
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

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 ]
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 ]
Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. [12724731 ]
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

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 ]
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 ]
Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. [12724731 ]
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

Type	Value	Assay Type	Assay Source
AC50	4.76 uM	Tox21_ELG1_LUC_Agonist	Tox21/NCGC

References

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

Type	Value	Assay Type	Assay Source
AC50	5.7 uM	OT_SRC1_SRC1FXR_1440	Odyssey Thera

References

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 ]

Fluorouracil (T3D4776)

Structure for T3D4776: Fluorouracil

Targets

References

References

References

Binding/Activity Constants

References

Binding/Activity Constants

References