Welcome to DrugBank 4.0! If you prefer, you can still go back to version 3.0.
Identification
NameTioguanine
Accession NumberDB00352  (APRD00290)
Typesmall molecule
Groupsapproved
Description

An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2-amino-1H-purine-6(7H)-thioneNot AvailableIUPAC
2-aminopurine-6-thiolNot AvailableWHO
ThioguanineNot AvailableUSAN
TioguaninGermanINN
TioguanineNot AvailableBAN, DCF, BP 2011
TioguaninumLatinINN
SaltsNot Available
Brand names
NameCompany
LanvisGlaxoSmithKline
TabloidGlaxoSmithKline
TioguaninaInduquimica
TioguanineIFET
Brand mixturesNot Available
Categories
CAS number154-42-7
WeightAverage: 167.192
Monoisotopic: 167.026565875
Chemical FormulaC5H5N5S
InChI KeyInChIKey=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)
IUPAC Name
2-amino-6,7-dihydro-3H-purine-6-thione
SMILES
NC1=NC(=S)C2=C(N1)N=CN2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassImidazopyrimidines
SubclassPurines and Purine Derivatives
Direct parentPurinethiones
Alternative parentsPyrimidinethiones; Primary Aromatic Amines; Imidazoles; Polyamines
Substituentspyrimidinethione; primary aromatic amine; pyrimidine; imidazole; azole; polyamine; primary amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the purinethiones. These are purines in which the purine moiety bears a thioketone.
Pharmacology
IndicationFor remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
PharmacodynamicsThioguanine 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 actionThioguanine 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.
AbsorptionAbsorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%)
Volume of distributionNot Available
Protein bindingNot 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.

SubstrateEnzymesProduct
Tioguanine
Thioguanosine monophosphateDetails
Thioguanosine monophosphate
Methyl-thioguanosine monophosphateDetails
Thioguanosine monophosphate
    Thioguanosine diphosphateDetails
    Thioguanosine diphosphate
      Thioguanosine triphosphateDetails
      Thioguanosine diphosphate
        Thiodeoxyguanosine diphosphateDetails
        Thiodeoxyguanosine diphosphate
          Thiodeoxyguanosine triphosphateDetails
          Route of eliminationNot Available
          Half lifeWhen the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 minutes)
          ClearanceNot Available
          ToxicityOral, mouse: LD50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis.
          Affected organisms
          • Humans and other mammals
          Pathways
          PathwayCategorySMPDB ID
          Thioguanine Action PathwayDrug actionSMP00430
          Thioguanine Metabolism PathwayDrug metabolismSMP00647
          SNP Mediated EffectsNot Available
          SNP Mediated Adverse Drug ReactionsNot Available
          ADMET
          Predicted ADMET features
          Property Value Probability
          Human Intestinal Absorption + 0.8857
          Blood Brain Barrier + 0.8663
          Caco-2 permeable - 0.5722
          P-glycoprotein substrate Non-substrate 0.7403
          P-glycoprotein inhibitor I Non-inhibitor 0.9168
          P-glycoprotein inhibitor II Non-inhibitor 0.9745
          Renal organic cation transporter Non-inhibitor 0.8499
          CYP450 2C9 substrate Non-substrate 0.8862
          CYP450 2D6 substrate Non-substrate 0.8332
          CYP450 3A4 substrate Non-substrate 0.7974
          CYP450 1A2 substrate Inhibitor 0.7904
          CYP450 2C9 substrate Non-inhibitor 0.6575
          CYP450 2D6 substrate Non-inhibitor 0.8881
          CYP450 2C19 substrate Inhibitor 0.5517
          CYP450 3A4 substrate Non-inhibitor 0.8309
          CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8537
          Ames test Non AMES toxic 0.7731
          Carcinogenicity Non-carcinogens 0.9255
          Biodegradation Not ready biodegradable 1.0
          Rat acute toxicity 2.1583 LD50, mol/kg Not applicable
          hERG inhibition (predictor I) Weak inhibitor 0.9743
          hERG inhibition (predictor II) Non-inhibitor 0.8918
          Pharmacoeconomics
          Manufacturers
          • Glaxosmithkline
          Packagers
          Dosage forms
          FormRouteStrength
          TabletOral40 mg
          Prices
          Unit descriptionCostUnit
          Thioguanine tabloid 40 mg tablet9.88USDeach
          Tabloid tablet9.44USDtablet
          DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
          PatentsNot Available
          Properties
          Statesolid
          Experimental Properties
          PropertyValueSource
          melting point>360 °CPhysProp
          water solubility36.3 mg/mLNot Available
          logP-0.07HANSCH,C ET AL. (1995)
          Predicted Properties
          PropertyValueSource
          water solubility8.34e-01 g/lALOGPS
          logP-0.36ALOGPS
          logP-0.35ChemAxon
          logS-2.3ALOGPS
          pKa (strongest acidic)10.53ChemAxon
          pKa (strongest basic)3.7ChemAxon
          physiological charge0ChemAxon
          hydrogen acceptor count4ChemAxon
          hydrogen donor count3ChemAxon
          polar surface area79.09ChemAxon
          rotatable bond count0ChemAxon
          refractivity46.89ChemAxon
          polarizability15.65ChemAxon
          number of rings2ChemAxon
          bioavailability1ChemAxon
          rule of fiveYesChemAxon
          Ghose filterNoChemAxon
          Veber's ruleNoChemAxon
          MDDR-like ruleNoChemAxon
          Spectra
          SpectraNot Available
          References
          Synthesis ReferenceNot Available
          General Reference
          1. FDA label
          External Links
          ResourceLink
          KEGG DrugD06109
          KEGG CompoundC07648
          PubChem Compound2723601
          PubChem Substance46508170
          ChemSpider2005804
          BindingDB50200099
          ChEBI9555
          ChEMBLCHEMBL727
          Therapeutic Targets DatabaseDAP000194
          PharmGKBPA451663
          Drug Product Database282081
          RxListhttp://www.rxlist.com/cgi/generic2/thioguanine.htm
          Drugs.comhttp://www.drugs.com/cdi/thioguanine.html
          WikipediaThioguanine
          ATC CodesL01BB03
          AHFS Codes
          • 10:00.00
          PDB Entries
          FDA labelshow(174 KB)
          MSDSshow(30.2 KB)
          Interactions
          Drug Interactions
          Drug
          Aminosalicylic AcidAminosalicylic acid may increase the toxicity of thiopurine, thioguanine.
          BusulfanBusulfan increases the hepatoxicity of Thioguanine during long-term concomitant therapy.
          MercaptopurineComplete cross resistance may occur.
          MesalazineMesalazine may increase the toxicity of thiopurine, thioguanine.
          NatalizumabThe immunosuppressant, Thioguanine, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
          OlsalazineOlsalazine may increase the toxicity of thiopurine, thioguanine.
          SulfasalazineSulfasalazine may increase the toxicity of thiopurine, thioguanine.
          TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
          Food InteractionsNot Available

          1. DNA

          Kind: nucleotide

          Organism: Human

          Pharmacological action: yes

          Actions: intercalation

          Components

          Name UniProt ID Details

          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

          1. Hypoxanthine-guanine phosphoribosyltransferase

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Hypoxanthine-guanine phosphoribosyltransferase P00492 Details

          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

          1. Multidrug resistance-associated protein 4

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Multidrug resistance-associated protein 4 O15439 Details

          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 March 19, 2014 12:03