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Identification
NameTioguanine
Accession NumberDB00352  (APRD00290)
TypeSmall Molecule
GroupsApproved
DescriptionAn antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. [PubChem]
Structure
Thumb
Synonyms
2-Amino 6mp
2-Amino-1,7-dihydro-6H-purine-6-thione
2-amino-1,9-Dihydropurine-6-thione
2-amino-1H-purine-6(7H)-thione
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-TG
6-Thioguanine
TG
ThG
Thioguanine
Tioguanin
Tioguanina
Tioguanine
Tioguaninum
External Identifiers
  • 6-TG
  • NSC 752
  • Wellcome U 3 B
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LanvisTablet40 mgOralAspen Pharma Trading Limited1974-12-31Not applicableCanada
TabloidTablet40 mg/1OralAspen Global Inc.2013-03-12Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
TioguaninaInduquimica
TioguanineIFET
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIWIX31ZPX66
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
Pharmacology
IndicationFor remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
Structured Indications
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.
TargetKindPharmacological actionActionsOrganismUniProt ID
DNANucleotideyes
intercalation
Humannot applicabledetails
Related Articles
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 Metabolism PathwayDrug metabolismSMP00647
Thioguanine Action PathwayDrug actionSMP00430
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Tioguanine.Approved
ALT-110The risk or severity of adverse effects can be increased when Tioguanine is combined with ALT-110.Investigational
AnvirzelAnvirzel may decrease the cardiotoxic activities of Tioguanine.Investigational
BalsalazideThe metabolism of Tioguanine can be decreased when combined with Balsalazide.Approved, Investigational
BcgThe therapeutic efficacy of Bcg can be decreased when used in combination with Tioguanine.Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Tioguanine.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Tioguanine.Approved
CDX-110The risk or severity of adverse effects can be increased when Tioguanine is combined with CDX-110.Investigational
ClozapineThe risk or severity of adverse effects can be increased when Tioguanine is combined with Clozapine.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Tioguanine.Approved, Investigational
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Tioguanine.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Tioguanine.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Tioguanine.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Tioguanine.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Tioguanine.Approved, Investigational
FingolimodTioguanine may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe risk or severity of adverse effects can be increased when Tioguanine is combined with G17DT.Investigational
GI-5005The risk or severity of adverse effects can be increased when Tioguanine is combined with GI-5005.Investigational
INGN 201The risk or severity of adverse effects can be increased when Tioguanine is combined with INGN 201.Investigational
INGN 225The risk or severity of adverse effects can be increased when Tioguanine is combined with INGN 225.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Tioguanine is combined with Leflunomide.Approved, Investigational
MesalazineThe metabolism of Tioguanine can be decreased when combined with Mesalazine.Approved
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Tioguanine.Withdrawn
NatalizumabThe risk or severity of adverse effects can be increased when Tioguanine is combined with Natalizumab.Approved, Investigational
OlsalazineThe metabolism of Tioguanine can be decreased when combined with Olsalazine.Approved
OuabainOuabain may decrease the cardiotoxic activities of Tioguanine.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Tioguanine.Approved, Vet Approved
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Tioguanine.Approved, Investigational
Rabies vaccineThe risk or severity of adverse effects can be increased when Tioguanine is combined with Rabies vaccine.Approved
Rabies vaccineThe therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Tioguanine.Approved
RoflumilastRoflumilast may increase the immunosuppressive activities of Tioguanine.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Tioguanine.Approved
SRP 299The risk or severity of adverse effects can be increased when Tioguanine is combined with SRP 299.Investigational
SulfasalazineThe metabolism of Tioguanine can be decreased when combined with Sulfasalazine.Approved
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Tioguanine.Approved, Investigational
TG4010The risk or severity of adverse effects can be increased when Tioguanine is combined with TG4010.Investigational
TofacitinibTioguanine may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Tioguanine.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesL01BB03
AHFS Codes
  • 10:00.00
PDB Entries
FDA labelDownload (174 KB)
MSDSDownload (30.2 KB)
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8857
Blood Brain Barrier+0.8663
Caco-2 permeable-0.5722
P-glycoprotein substrateNon-substrate0.7403
P-glycoprotein inhibitor INon-inhibitor0.9168
P-glycoprotein inhibitor IINon-inhibitor0.9745
Renal organic cation transporterNon-inhibitor0.8499
CYP450 2C9 substrateNon-substrate0.8862
CYP450 2D6 substrateNon-substrate0.8332
CYP450 3A4 substrateNon-substrate0.7974
CYP450 1A2 substrateInhibitor0.7904
CYP450 2C9 inhibitorNon-inhibitor0.6575
CYP450 2D6 inhibitorNon-inhibitor0.8881
CYP450 2C19 inhibitorInhibitor0.5517
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8537
Ames testNon AMES toxic0.7731
CarcinogenicityNon-carcinogens0.9255
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.1583 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9743
hERG inhibition (predictor II)Non-inhibitor0.8918
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
Packagers
Dosage forms
FormRouteStrength
TabletOral40 mg
TabletOral40 mg/1
Prices
Unit descriptionCostUnit
Thioguanine tabloid 40 mg tablet9.88USD each
Tabloid tablet9.44USD tablet
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 Solubility0.834 mg/mLALOGPS
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 Area79.09 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity46.89 m3·mol-1ChemAxon
Polarizability15.65 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as purinethiones. These are purines in which the purine moiety bears a thioketone.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassImidazopyrimidines
Sub ClassPurines and purine derivatives
Direct ParentPurinethiones
Alternative Parents
Substituents
  • Purinethione
  • Pyrimidinethione
  • Pyrimidine
  • Primary aromatic amine
  • Heteroaromatic compound
  • Imidazole
  • Azole
  • Azacycle
  • Hydrocarbon derivative
  • Primary amine
  • Organosulfur compound
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
intercalation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Schwartz EL, Ishiguro K, Sartorelli AC: Induction of leukemia cell differentiation by chemotherapeutic agents. Adv Enzyme Regul. 1983;21:3-20. [PubMed:6400065 ]
  2. Riscoe MK, Brouns MC, Fitchen JH: Purine metabolism as a target for leukemia chemotherapy. Blood Rev. 1989 Sep;3(3):162-73. [PubMed:2676034 ]
  3. Sahasranaman S, Howard D, Roy S: Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. doi: 10.1007/s00228-008-0478-6. Epub 2008 May 28. [PubMed:18506437 ]
  4. Coulthard S, Hogarth L: The thiopurines: an update. Invest New Drugs. 2005 Dec;23(6):523-32. [PubMed:16267626 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Protein homodimerization activity
Specific Function:
Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
Gene Name:
HPRT1
Uniprot ID:
P00492
Molecular Weight:
24579.155 Da
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:11545274 ]
  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:11756148 ]
  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:1383700 ]
  4. Elgemeie GH: Thioguanine, mercaptopurine: their analogs and nucleosides as antimetabolites. Curr Pharm Des. 2003;9(31):2627-42. [PubMed:14529546 ]
  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:15136753 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Atpase activity, coupled to transmembrane movement of substances
Specific Function:
May be an organic anion pump relevant to cellular detoxification.
Gene Name:
ABCC4
Uniprot ID:
O15439
Molecular Weight:
149525.33 Da
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:14643890 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23