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Record Information
Version4.0
StatusExpected but not Quantified
Creation Date2012-09-06 15:16:49 UTC
Update Date2017-12-07 02:45:42 UTC
HMDB IDHMDB0014438
Secondary Accession Numbers
  • HMDB14438
Metabolite Identification
Common NameRaltitrexed
DescriptionRaltitrexed is only found in individuals that have used or taken this drug. It is a chemotherapy drug manufactured AstraZeneca Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.Raltitrexed is an antineoplastic Agents and folic acid antagonists. Raltitrexed inhibits thymidylate synthase (TS) leading to DNA fragmentation and cell death. It is transported into cells via a reduced folate carrier. Inside the cell Raltitrexed is extensively polyglutamated, which enhances thymidylate synthase inhibitory power and duration. Inhibition of this enzyme results in decreased synthesis of thymidine triphosphate which is required for DNA synthesis.
Structure
Thumb
Synonyms
ValueSource
ZD1694Kegg
TomudexKegg
ZD-1694HMDB
ICI-D1694MeSH
N-(5-(N-(3,4-dihydro-2-Methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)-L-glutamic acidMeSH
Arkomédika brand OF raltitrexedMeSH
AstraZeneca brand OF raltitrexedMeSH
ICI D1694MeSH
Zeneca brand OF raltitrexedMeSH
Chemical FormulaC21H22N4O6S
Average Molecular Weight458.488
Monoisotopic Molecular Weight458.126005146
IUPAC Name(2S)-2-[(5-{methyl[(2-methyl-4-oxo-1,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid
Traditional Nameraltitrexed
CAS Registry Number112887-68-0
SMILES
CN(CC1=CC2=C(NC(C)=NC2=O)C=C1)C1=CC=C(S1)C(=O)N[C@@H](CCC(O)=O)C(O)=O
InChI Identifier
InChI=1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1
InChI KeyIVTVGDXNLFLDRM-HNNXBMFYSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganic acids and derivatives
Sub ClassCarboxylic acids and derivatives
Direct ParentGlutamic acid and derivatives
Alternative Parents
Substituents
  • Glutamic acid or derivatives
  • N-acyl-alpha-amino acid
  • N-acyl-alpha amino acid or derivatives
  • Diazanaphthalene
  • Quinazoline
  • 2-heteroaryl carboxamide
  • Thiophene carboxamide
  • Thiophene carboxylic acid or derivatives
  • Dialkylarylamine
  • Hydroxypyrimidine
  • 2,5-disubstituted thiophene
  • Pyrimidine
  • Dicarboxylic acid or derivatives
  • 2-aminothiophene
  • Benzenoid
  • Heteroaromatic compound
  • Thiophene
  • Carboxamide group
  • Secondary carboxylic acid amide
  • Azacycle
  • Carboxylic acid
  • Organoheterocyclic compound
  • Carbonyl group
  • Organooxygen compound
  • Organonitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Ontology
Disposition

Biological Location:

  Subcellular:

  Biofluid and excreta:

Role

Industrial application:

  Pharmaceutical industry:

Biological role:

Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point180 - 184 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.018 g/LNot Available
LogP-1.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.018 g/LALOGPS
logP1.65ALOGPS
logP1.97ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.72ChemAxon
pKa (Strongest Basic)-0.46ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area148.4 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity117.39 m³·mol⁻¹ChemAxon
Polarizability45.55 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-03dl-2443900000-4123f916ebf757efa490View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-00dr-7321290000-bce279f690f228594cb4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-03k9-0709000000-b0a922c0009fee349863View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-074l-0512900000-f514d4a6b300e1598c10View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0h90-0932200000-df9ed4d0d58576d2bb3fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00di-0910000000-639daf8403905e6f1108View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0290000000-b82035dbae7250dd815aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0bvj-0695700000-22b802197672293574e8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0r09-6940000000-c21b12820e7259aeaa79View in MoNA
Biological Properties
Cellular Locations
  • Cytoplasm
Biofluid Locations
  • Blood
  • Urine
Tissue LocationNot Available
PathwaysNot Available
NameSMPDB/PathwhizKEGG
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB00293 details
UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB00293 details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB00293
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID94568
KEGG Compound IDC11372
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkRaltitrexed
METLIN IDNot Available
PubChem Compound104758
PDB IDD16
ChEBI IDNot Available
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General ReferencesNot Available

Enzymes

General function:
Involved in tetrahydrofolylpolyglutamate synthase activity
Specific function:
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstitued reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.
Gene Name:
FPGS
Uniprot ID:
Q05932
Molecular weight:
59173.37
References
  1. Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer. 2002 Mar;38(5):639-44. [PubMed:11916544 ]
General function:
Involved in thymidylate synthase activity
Specific function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:
TYMS
Uniprot ID:
P04818
Molecular weight:
35715.65
References
  1. Yin MB, Guo B, Panadero A, Frank C, Wrzosek C, Slocum HK, Rustum YM: Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. Exp Cell Res. 1999 Feb 25;247(1):189-99. [PubMed:10047461 ]
  2. Cao S, McGuire JJ, Rustum YM: Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. Clin Cancer Res. 1999 Jul;5(7):1925-34. [PubMed:10430100 ]
  3. Ferguson PJ, Collins O, Dean NM, DeMoor J, Li CS, Vincent MD, Koropatnick J: Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 1999 Aug;127(8):1777-86. [PubMed:10482907 ]
  4. Orlandi L, Bearzatto A, Abolafio G, De Marco C, Daidone MG, Zaffaroni N: Involvement of bcl-2 and p21waf1 proteins in response of human breast cancer cell clones to Tomudex. Br J Cancer. 1999 Sep;81(2):252-60. [PubMed:10496350 ]
  5. Grem JL, Sorensen JM, Cullen E, Takimoto CH, Steinberg SM, Chen AP, Hamilton JM, Arbuck SG, McAtee N, Lawrence D, Goldspiel B, Johnston PG, Allegra CJ: A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors. Clin Cancer Res. 1999 Sep;5(9):2381-91. [PubMed:10499608 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Yang Z, Waldman AS, Wyatt MD: DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. doi: 10.1016/j.bcp.2008.08.010. Epub 2008 Aug 19. [PubMed:18773878 ]
  8. Chen VJ, Bewley JR, Andis SL, Schultz RM, Iversen PW, Shih C, Mendelsohn LG, Seitz DE, Tonkinson JL: Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol. 1999 Apr;26(2 Suppl 6):48-54. [PubMed:10598555 ]
  9. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]