Tioguanine

Identification

Summary

Tioguanine is a purine analogue antineoplastic agent used for the induction of remission, and for remission consolidation in patients with acute nonlymphocytic anemias.

Brand Names
Lanvis, Tabloid
Generic Name
Tioguanine
DrugBank Accession Number
DB00352
Background

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

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 167.192
Monoisotopic: 167.026565875
Chemical Formula
C5H5N5S
Synonyms
  • 2-Amino 6MP
  • 2-Amino-1,7-dihydro-6H-purine-6-thione
  • 2-amino-1,9-dihydropurine-6-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
  • Thioguanine anhydrous
  • Thioguanine, anhydrous
  • Tioguanin
  • Tioguanina
  • Tioguanine
  • Tioguaninum
External IDs
  • 6-TG
  • NSC 752
  • NSC-752
  • NSC-76504
  • Wellcome U 3 B

Pharmacology

Indication

For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
ADNA
intercalation
Humans
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.

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Route of elimination

Not Available

Half-life

When 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)

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Oral, mouse: LD50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis.

Pathways
PathwayCategory
Thioguanine Action PathwayDrug action
Thioguanine Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Thiopurine S-methyltransferaseTPMT*2(G;G) / (C;G)G AlleleADR Directly StudiedThe presence of this polymorphism in TPMT may be associated with an increased risk of developing rapid bone marrow suppression when treated with tioguanine.Details
Thiopurine S-methyltransferaseTPMT*3A(A;A) / (A;G)A AlleleADR Directly StudiedThe presence of this polymorphism in TPMT may be associated with an increased risk of developing rapid bone marrow suppression when treated with tioguanine.Details
Thiopurine S-methyltransferaseTPMT*3C(G;G) / (A;G)G AlleleADR Directly StudiedThe presence of this polymorphism in TPMT may be associated with an increased risk of developing rapid bone marrow suppression when treated with tioguanine.Details
Thiopurine S-methyltransferaseTPMT*4A(A;A) / (A;G)G > AADR Directly StudiedThe presence of this polymorphism in TPMT may be associated with an increased risk of developing rapid bone marrow suppression when treated with tioguanine.Details
Thiopurine S-methyltransferaseTPMT*3BNot Availablec.460G>AADR InferredSevere myelosuppression.Details

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Tioguanine is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Tioguanine.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Tioguanine.
Acetylsalicylic acidThe metabolism of Tioguanine can be decreased when combined with Acetylsalicylic acid.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Tioguanine.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Tioguanine.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Tioguanine.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Tioguanine.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Tioguanine.
Allogeneic processed thymus tissueThe therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Tioguanine.
Interactions
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Food Interactions
  • Take with or without food. However, food intake may lower tioguanine serum levels.

Products

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Product Images
International/Other Brands
Tioguanina (Induquimica) / Tioguanine (IFET)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LanvisTablet40 mgOralAspen Pharmacare Canada Inc.1974-12-31Not applicableCanada flag
TabloidTablet40 mg/1OralAspen Global Inc.2013-03-12Not applicableUS flag
TabloidTablet40 mg/1OralGlaxosmithkline Inc1984-12-182014-10-31US flag0173 088020180907 15195 19hbjkn

Categories

ATC Codes
L01BB03 — Tioguanine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as purinethiones. These are purines in which the purine moiety bears a thioketone.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyrimidines
Sub Class
Purines and purine derivatives
Direct Parent
Purinethiones
Alternative Parents
Pyrimidinethiones / Aminopyrimidines and derivatives / Imidazoles / Heteroaromatic compounds / Azacyclic compounds / Primary amines / Organosulfur compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Amine / Aminopyrimidine / Aromatic heteropolycyclic compound / Azacycle / Azole / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Organic nitrogen compound / Organonitrogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
2-aminopurines (CHEBI:9555)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
WIX31ZPX66
CAS number
154-42-7
InChI Key
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

References

General References
Not Available
Human Metabolome Database
HMDB0014496
KEGG Drug
D08603
KEGG Compound
C07648
PubChem Compound
2723601
PubChem Substance
46508170
ChemSpider
2005804
BindingDB
50200099
RxNav
10485
ChEBI
9555
ChEMBL
CHEMBL727
ZINC
ZINC000006382803
Therapeutic Targets Database
DAP000194
PharmGKB
PA451663
PDBe Ligand
DX4
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tioguanine
PDB Entries
3jqa / 3rkf / 4m5m / 4xoy / 4xp3 / 5xu8
FDA label
Download (174 KB)
MSDS
Download (30.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentLeukemia, Lymphocytic, Acute, Adult3
4CompletedTreatmentLymphoma, Lymphoblastic1
4Unknown StatusTreatmentAcute Lymphoblastic Leukemia (ALL)1
4Unknown StatusTreatmentLeukemia, Lymphocytic, Acute, Adult1
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL)1
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL) / Adult B Lymphoblastic Lymphoma / Ann Arbor Stage I B Lymphoblastic Lymphoma / Ann Arbor Stage II B Lymphoblastic Lymphoma / Childhood B Acute Lymphoblastic Leukemia / Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 / Childhood B Lymphoblastic Lymphoma / Down Syndrome (DS) / Hypodiploid B Acute Lymphoblastic Leukemia / Philadelphia Chromosome Positive1
3Active Not RecruitingTreatmentAdult T Acute Lymphoblastic Leukemia / Ann Arbor Stage II Adult Lymphoblastic Lymphoma / Ann Arbor Stage II Childhood Lymphoblastic Lymphoma / Ann Arbor Stage III Adult Lymphoblastic Lymphoma / Ann Arbor Stage III Childhood Lymphoblastic Lymphoma / Ann Arbor Stage IV Adult Lymphoblastic Lymphoma / Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma / Childhood T Acute Lymphoblastic Leukemia1
3Active Not RecruitingTreatmentB Acute Lymphoblastic Leukemia / Central Nervous System Leukemia / Ph-Like Acute Lymphoblastic Leukemia / Testicular Leukemia1
3Active Not RecruitingTreatmentChildhood Acute Basophilic Leukemia / Childhood Acute Eosinophilic Leukemia / Childhood Acute Erythroleukemia (M6) / Childhood Acute Megakaryocytic Leukemia (M7) / Childhood Acute Minimally Differentiated Myeloid Leukemia (M0) / Childhood Acute Monoblastic Leukemia (M5a) / Childhood Acute Monocytic Leukemia (M5b) / Childhood Acute Myeloblastic Leukemia With Maturation (M2) / Childhood Acute Myeloblastic Leukemia Without Maturation (M1) / Childhood Acute Myelomonocytic Leukemia (M4) / Childhood Myelodysplastic Syndromes / De Novo Myelodysplastic Syndromes / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Secondary Myelodysplastic Syndromes / Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies1
3Active Not RecruitingTreatmentLeukemias1

Pharmacoeconomics

Manufacturers
  • Glaxosmithkline
Packagers
  • DSM Corp.
  • GlaxoSmithKline Inc.
Dosage Forms
FormRouteStrength
TabletOral40 mg
TabletOral40 mg/1
TabletOral
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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Nucleotide
Organism
Humans
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.
References
  1. Schwartz EL, Ishiguro K, Sartorelli AC: Induction of leukemia cell differentiation by chemotherapeutic agents. Adv Enzyme Regul. 1983;21:3-20. [Article]
  2. Riscoe MK, Brouns MC, Fitchen JH: Purine metabolism as a target for leukemia chemotherapy. Blood Rev. 1989 Sep;3(3):162-73. [Article]
  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. [Article]
  4. Coulthard S, Hogarth L: The thiopurines: an update. Invest New Drugs. 2005 Dec;23(6):523-32. [Article]

Enzymes

Kind
Protein
Organism
Humans
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...
Gene Name
HPRT1
Uniprot ID
P00492
Uniprot Name
Hypoxanthine-guanine phosphoribosyltransferase
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. [Article]
  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. [Article]
  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. [Article]
  4. Elgemeie GH: Thioguanine, mercaptopurine: their analogs and nucleosides as antimetabolites. Curr Pharm Des. 2003;9(31):2627-42. [Article]
  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. [Article]

Transporters

Kind
Protein
Organism
Humans
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
Uniprot Name
Multidrug resistance-associated protein 4
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. [Article]

Drug created on June 13, 2005 13:24 / Updated on October 20, 2021 19:48