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
Structure for Tirapazamine (DB04858)
- 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
Pharmacology
- Indication
For the treatment of head and neck cancer.
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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.
Target Actions Organism UDNA Not Available Humans - 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
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.
Drug Interaction Integrate drug-drug
interactions in your softwareAmbroxol The risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Ambroxol. Articaine The risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Articaine. Benzocaine The risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Benzocaine. Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Benzyl alcohol. Bupivacaine The risk or severity of methemoglobinemia can be increased when Tirapazamine is combined with Bupivacaine. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- 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
- Denny WA: Prospects for hypoxia-activated anticancer drugs. Curr Med Chem Anticancer Agents. 2004 Sep;4(5):395-9. [Article]
- 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]
- 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]
- External Links
- 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
Phase Status Purpose Conditions Count 3 Completed Treatment Head and Neck Neoplasms 1 3 Completed Treatment Lung Cancer 2 3 Completed Treatment Squamous Cell Carcinoma of the Head and Neck (SCCHN) 1 3 Terminated Treatment Cervical 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 Cancer 1 2 Completed Treatment Cervical Cancer 1
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
Property Value Source Water Solubility 3.93 mg/mL ALOGPS logP -0.21 ALOGPS logP -0.29 Chemaxon logS -1.7 ALOGPS pKa (Strongest Acidic) 12.97 Chemaxon pKa (Strongest Basic) 2.18 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 92.79 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 56.94 m3·mol-1 Chemaxon Polarizability 15.97 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.7534 Blood Brain Barrier + 0.8055 Caco-2 permeable - 0.5073 P-glycoprotein substrate Non-substrate 0.6092 P-glycoprotein inhibitor I Non-inhibitor 0.8876 P-glycoprotein inhibitor II Non-inhibitor 0.9664 Renal organic cation transporter Non-inhibitor 0.8659 CYP450 2C9 substrate Non-substrate 0.7746 CYP450 2D6 substrate Non-substrate 0.8235 CYP450 3A4 substrate Non-substrate 0.5581 CYP450 1A2 substrate Inhibitor 0.6016 CYP450 2C9 inhibitor Non-inhibitor 0.6654 CYP450 2D6 inhibitor Non-inhibitor 0.8474 CYP450 2C19 inhibitor Non-inhibitor 0.662 CYP450 3A4 inhibitor Non-inhibitor 0.921 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7748 Ames test AMES toxic 0.7746 Carcinogenicity Non-carcinogens 0.8875 Biodegradation Not ready biodegradable 0.9644 Rat acute toxicity 2.5331 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.5063 hERG inhibition (predictor II) Non-inhibitor 0.7149
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 128.84315 predictedDeepCCS 1.0 (2019) [M+H]+ 131.24171 predictedDeepCCS 1.0 (2019) [M+Na]+ 137.5548 predictedDeepCCS 1.0 (2019)
Targets
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Unknown
Enzymes
- 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
- 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