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Identification
Name Thioguanine
Accession Number DB00352 (APRD00290)
Type small molecule
Groups approved
Description

An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
2-Amino 6MP
2-Amino-6-mercaptopurine
2-Amino-6-merkaptopurin
2-Amino-6-purinethiol
2-Aminopurin-6-thiol
2-Aminopurine-6-thiol
2-Aminopurine-6(1H)-thione
6-Mercapto-2-aminopurine
6-Mercaptoguanine
6-Thioguanine
TG
ThG
Tioguanin
Tioguanine
First Prev Next Last
Salts Not Available
Brand names
Name Company
Lanvis
Tabloid
Wellcome U3B
Brand mixtures Not Available
Categories
  • Antimetabolites, Antineoplastic
CAS number 154-42-7
Weight Average: 167.192
Monoisotopic: 167.026565875
Chemical Formula C5H5N5S
InChI Key InChIKey=WYWHKKSPHMUBEB-UHFFFAOYSA-N
InChI
InChI=1S/C5H5N5S/c6-5-9-3-2(4(11)10-5)7-1-8-3/h1H,(H4,6,7,8,9,10,11)
Plain Text
IUPAC Name
2-amino-6,7-dihydro-3H-purine-6-thione
SMILES
NC1=NC(=S)C2=C(N1)N=CN2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Purines and Purine Derivatives
Substructures
  • Aliphatic and Aryl Amines
  • Pyrimidines and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Purines and Purine Derivatives
  • Cyanamides
Pharmacology
Indication For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
Pharmacodynamics Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase).
Mechanism of action Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides.
Absorption Absorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%)
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides.
Route of elimination Not Available
Half life 80 minutes (range 25-240 minutes)
Clearance Not Available
Toxicity Oral, mouse: LD50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00430 Thioguanine Pathway SMP00430
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Thioguanine tabloid 40 mg tablet 9.88 USD each
Tabloid tablet 9.44 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point >360 °C PhysProp
water solubility 36.3 mg/mL Not Available
logP -0.07 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 8.34e-01 g/l ALOGPS
logP -0.36 ALOGPS
logP -0.35 ChemAxon
logS -2.3 ALOGPS
pKa (strongest acidic) 10.53 ChemAxon
pKa (strongest basic) 3.7 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 79.09 ChemAxon
rotatable bond count 0 ChemAxon
refractivity 46.89 ChemAxon
polarizability 15.65 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07648 Link_out
PubChem Compound 2723601 Link_out
PubChem Substance 46508170 Link_out
ChemSpider 2005804 Link_out
BindingDB 50200099 Link_out
Therapeutic Targets Database DAP000194 Link_out
PharmGKB PA451663 Link_out
Drug Product Database 282081 Link_out
RxList http://www.rxlist.com/cgi/generic2/thioguanine.htm Link_out
Drugs.com http://www.drugs.com/cdi/thioguanine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Thioguanine Link_out
ATC Codes
  • L01BB03
AHFS Codes
  • 10:00.00
PDB Entries
FDA label show (174 KB)
MSDS show (30.2 KB)
Interactions
Drug Interactions
Drug Interaction
Aminosalicylic Acid Aminosalicylic acid may increase the toxicity of thiopurine, thioguanine.
Busulfan Busulfan increases the hepatoxicity of Thioguanine during long-term concomitant therapy.
Mercaptopurine Complete cross resistance may occur.
Mesalazine Mesalazine may increase the toxicity of thiopurine, thioguanine.
Natalizumab The immunosuppressant, Thioguanine, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
Olsalazine Olsalazine may increase the toxicity of thiopurine, thioguanine.
Sulfasalazine Sulfasalazine may increase the toxicity of thiopurine, thioguanine.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available
Targets

1. DNA

Pharmacological action: yes
Actions: intercalation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

References:
  1. Schwartz EL, Ishiguro K, Sartorelli AC: Induction of leukemia cell differentiation by chemotherapeutic agents. Adv Enzyme Regul. 1983;21:3-20. Pubmed
  2. Riscoe MK, Brouns MC, Fitchen JH: Purine metabolism as a target for leukemia chemotherapy. Blood Rev. 1989 Sep;3(3):162-73. Pubmed
  3. Sahasranaman S, Howard D, Roy S: Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. Epub 2008 May 28. Pubmed
  4. Coulthard S, Hogarth L: The thiopurines: an update. Invest New Drugs. 2005 Dec;23(6):523-32. Pubmed
Enzymes

1. Hypoxanthine-guanine phosphoribosyltransferase

Actions: substrate
UniProt ID: P00492 Link_out
Gene: HPRT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Shivashankar K, Subbayya IN, Balaram H: Development of a bacterial screen for novel hypoxanthine-guanine phosphoribosyltransferase substrates. J Mol Microbiol Biotechnol. 2001 Oct;3(4):557-62. Pubmed
  2. Horikawa K, Kawaguchi T, Ishihara S, Nagakura S, Hidaka M, Kagimoto T, Mitsuya H, Nakakuma H: Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2002 Jan 1;99(1):24-9. Pubmed
  3. Fuscoe JC, Zimmerman LJ, Fekete A, Setzer RW, Rossiter BJ: Analysis of X-ray-induced HPRT mutations in CHO cells: insertion and deletions. Mutat Res. 1992 Oct;269(2):171-83. Pubmed
  4. Elgemeie GH: Thioguanine, mercaptopurine: their analogs and nucleosides as antimetabolites. Curr Pharm Des. 2003;9(31):2627-42. Pubmed
  5. Suzuki M, Tsuruoka C, Kanai T, Kato T, Yatagai F, Watanabe M: Qualitative and quantitative difference in mutation induction between carbon- and neon-ion beams in normal human cells. Biol Sci Space. 2003 Dec;17(4):302-6. Pubmed
Transporters

1. Multidrug resistance-associated protein 4

Actions: inhibitor

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bai J, Lai L, Yeo HC, Goh BC, Tan TM: Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19