NAV

Tirapazamine

Identification

Generic Name
Tirapazamine
DrugBank Accession Number
DB04858
Background

Tirapazamine, also known as SR-4233, is an experimental anticancer drug that is activated in hypoxic conditions. This activation is very useful as this hypoxic state is found in human solid tumors in a common phenomenon known as tumor hypoxia. Hence, tirapazamine is solely activated in those hypoxic areas of solid tumors. It is important to take into consideration that normally, the cells in these hypoxic regions are resistant to radiotherapy and most anticancer drugs. For all these reasons, the combination of tirapazamine with other anticancer treatments is highly recommended.

Tirapazamine entered phase III testing in 2006 for patients with head and neck cancer and gynecological cancer, as well as for other solid tumor cancer types.

Type
Small Molecule
Groups
Investigational
Structure
Similar Structures
Weight
Average: 178.151
Monoisotopic: 178.049075449
Chemical Formula
C7H6N4O2
Synonyms
  • 1,2,4-benzotriazin-3-amine, 1,4-dioxide
  • 3-Amino-1,2,4-benzotriazine 1,4-dioxide
  • Tirapazamine
External IDs
  • SR 4233
  • SR-259075
  • SR-4233
  • SR259075
  • WIN 59075
  • WIN-59075
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Pharmacology

Indication

For the treatment of head and neck cancer.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Tirapazamine is a anticancer drug that is inactive in normal tissues that are well oxygenated, but becomes active at the low oxygen levels found in solid tumors. As a result, the drug kills these poorly oxygenated or hypoxic cells while limiting toxicity in normal tissue. Tirapazamine may prove highly effective when used in combination with standard anticancer therapy, as these hypoxic cells are characteristically resistant to radiation and common anticancer agents.

Mechanism of action

Extensive preclinical testing has established that the mechanism for the selective toxicity towards hypoxic cells is the result of a one-electron reduction of the parent molecule to a free radical species that interacts with DNA to produce single- and double-strand breaks and lethal chromosome aberrations. It has also shown activity when combined with fractionated irradiation and when combined with some chemotherapy agents, particularly cisplatin and carboplatin.

TargetActionsOrganism
UDNANot AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
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interactions in your software
AmbroxolThe risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Bupivacaine.
Food Interactions
Not Available

Products

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International/Other Brands
Tirazone (Sanofi-aventis)

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as aminotriazines. These are organic compounds containing an amino group attached to a triazine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Triazines
Sub Class
Aminotriazines
Direct Parent
Aminotriazines
Alternative Parents
Benzenoids / 1,2,4-triazines / Heteroaromatic compounds / Azacyclic compounds / Primary amines / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
1,2,4-triazine / Amine / Aminotriazine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic amine, N-oxide, benzotriazines (CHEBI:78887)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1UD32YR59G
CAS number
27314-97-2
InChI Key
ORYDPOVDJJZGHQ-UHFFFAOYSA-N
InChI
InChI=1S/C7H6N4O2/c8-7-9-11(13)6-4-2-1-3-5(6)10(7)12/h1-4H,(H2,8,9)
IUPAC Name
3-amino-1,2,4-benzotriazine-1,4-diium-1,4-bis(olate)
SMILES
NC1=[N+]([O-])C2=C(C=CC=C2)[N+]([O-])=N1

References

General References
  1. Denny WA: Prospects for hypoxia-activated anticancer drugs. Curr Med Chem Anticancer Agents. 2004 Sep;4(5):395-9. [Article]
  2. Gandara DR, Lara PN Jr, Goldberg Z, Le QT, Mack PC, Lau DH, Gumerlock PH: Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. Semin Oncol. 2002 Feb;29(1 Suppl 4):102-9. [Article]
  3. Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WW: SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1239-42. [Article]
KEGG Drug
D06167
PubChem Compound
33776
PubChem Substance
175426868
ChemSpider
10437748
BindingDB
50226806
ChEBI
78887
ChEMBL
CHEMBL50882
ZINC
ZINC000001607808
Wikipedia
Tirapazamine

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHead and Neck Neoplasms1
3CompletedTreatmentLung Cancer2
3CompletedTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
3TerminatedTreatmentCervical Adenocarcinoma / Cervical Adenosquamous Cell Carcinoma / Cervical Cancer Stage IIa / Cervical Cancer, Stage IIB / Cervical Cancer, Stage III / Cervical Cancer, Stage IVA / Cervical Squamous Cell Carcinoma / Stage IB Cervical Cancer1
2CompletedTreatmentCervical Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility3.93 mg/mLALOGPS
logP-0.21ALOGPS
logP-0.29Chemaxon
logS-1.7ALOGPS
pKa (Strongest Acidic)12.97Chemaxon
pKa (Strongest Basic)2.18Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area92.79 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity56.94 m3·mol-1Chemaxon
Polarizability15.97 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.7534
Blood Brain Barrier+0.8055
Caco-2 permeable-0.5073
P-glycoprotein substrateNon-substrate0.6092
P-glycoprotein inhibitor INon-inhibitor0.8876
P-glycoprotein inhibitor IINon-inhibitor0.9664
Renal organic cation transporterNon-inhibitor0.8659
CYP450 2C9 substrateNon-substrate0.7746
CYP450 2D6 substrateNon-substrate0.8235
CYP450 3A4 substrateNon-substrate0.5581
CYP450 1A2 substrateInhibitor0.6016
CYP450 2C9 inhibitorNon-inhibitor0.6654
CYP450 2D6 inhibitorNon-inhibitor0.8474
CYP450 2C19 inhibitorNon-inhibitor0.662
CYP450 3A4 inhibitorNon-inhibitor0.921
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7748
Ames testAMES toxic0.7746
CarcinogenicityNon-carcinogens0.8875
BiodegradationNot ready biodegradable0.9644
Rat acute toxicity2.5331 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5063
hERG inhibition (predictor II)Non-inhibitor0.7149
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 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-128.84315
predicted
DeepCCS 1.0 (2019)
[M+H]+131.24171
predicted
DeepCCS 1.0 (2019)
[M+Na]+137.5548
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. DNA
Kind
Nucleotide
Organism
Humans
Pharmacological action
Unknown
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.

Enzymes

Details1. Cytochrome P450 2E1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Khan S, O'Brien PJ: Molecular mechanisms of tirapazamine (SR 4233, Win 59075)-induced hepatocyte toxicity under low oxygen concentrations. Br J Cancer. 1995 Apr;71(4):780-5. [Article]

Drug created at October 19, 2007 00:36 / Updated at January 14, 2023 19:02