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Identification
Name Raltitrexed
Accession Number DB00293 (APRD00430, EXPT01092)
Type small molecule
Groups approved
Description

Raltitrexed (brand name Tomudex®) is a chemotherapy drug manufactured AstraZeneca Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
ZD-1694
ZD1694
Salts Not Available
Brand names
Name Company
Tomudex
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antimetabolites
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Antimetabolites, Antineoplastic
CAS number 112887-68-0
Weight Average: 458.488
Monoisotopic: 458.126005146
Chemical Formula C21H22N4O6S
InChI Key InChIKey=IVTVGDXNLFLDRM-HNNXBMFYSA-N
InChI
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
Plain Text
IUPAC Name
(2S)-2-[(5-{methyl[(2-methyl-4-oxo-1,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Quinazolines
Substructures
  • Hydroxy Compounds
  • Quinazolines
  • Acetates
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Pyrimidines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • Cyanamides
  • Thiophenes
Pharmacology
Indication For the treatment of malignant neoplasm of colon and rectum
Pharmacodynamics Raltitrexed belongs to a group of medicines known as antimetabolites. It is used to treat cancer of the colon and rectum. It may also be used to treat other kinds of cancer, as determined by your doctor. Raltitrexed blocks an enzyme needed by the cell to live. This interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by raltitrexed, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern.
Mechanism of action 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding >93%
Metabolism Raltitrexed is transported into cells via a reduced folate carrier. Inside the cell it is extensively polyglutamated by the enzyme folyl polyglutamate synthetase to polyglutamate forms.
Route of elimination Not Available
Half life 198 hours
Clearance Not Available
Toxicity Side effects include pale skin, troubled breathing, unusual bleeding or bruising, unusual tiredness or weakness, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, increase in bowel movements, loose stools, soft stools.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 180-184 °C Not Available
water solubility soluble Not Available
logP -1.2 Not Available
Predicted Properties
Property Value Source
water solubility 1.81e-02 g/l ALOGPS
logP 1.65 ALOGPS
logP 1.97 ChemAxon
logS -4.4 ALOGPS
pKa (strongest acidic) 3.72 ChemAxon
pKa (strongest basic) -0.46 ChemAxon
physiological charge -2 ChemAxon
hydrogen acceptor count 9 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 148.4 ChemAxon
rotatable bond count 9 ChemAxon
refractivity 117.39 ChemAxon
polarizability 45.55 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01064 Link_out
KEGG Compound C11372 Link_out
PubChem Compound 104758 Link_out
PubChem Substance 46504880 Link_out
ChemSpider 94568 Link_out
BindingDB 18795 Link_out
Therapeutic Targets Database DAP000759 Link_out
PharmGKB PA131625240 Link_out
HET D16 Link_out
Drug Product Database 2229566 Link_out
Wikipedia http://en.wikipedia.org/wiki/Raltitrexed Link_out
ATC Codes
  • L01BA03
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label Not Available
MSDS show (57 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Thymidylate synthase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P04818 Link_out
Gene: TYMS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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. Epub 2008 Aug 19. Pubmed
  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
  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

2. Folylpolyglutamate synthase, mitochondrial

Pharmacological action: unknown
Actions: antagonist

Conversion of folates to polyglutamate derivatives. This allows tissues to concentrate folate at higher levels than in plasma

Organism class: human
UniProt ID: Q05932 Link_out
Gene: FPGS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer. 2002 Mar;38(5):639-44. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19