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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 KeyWYWHKKSPHMUBEB-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
Not Available
Thioguanosine diphosphateDetails
Thioguanosine diphosphate
Not Available
Thioguanosine triphosphateDetails
Thioguanosine diphosphate
Not Available
Thiodeoxyguanosine diphosphateDetails
Thiodeoxyguanosine diphosphate
Not Available
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

Targets

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

Enzymes

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

Transporters

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

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Drug created on June 13, 2005 07:24 / Updated on March 19, 2014 12:03