Identification

Name
Tirapazamine
Accession Number
DB04858
Type
Small Molecule
Groups
Investigational
Description

Tirapazamine (SR-4233) is an experimental anticancer drug that is activated to a toxic radical only at very low levels of oxygen (hypoxia). Such levels are common in human solid tumors, a phenomenon known as tumor hypoxia. Thus, tirapazamine is activated to its toxic form preferentially in the hypoxic areas of solid tumors. Cells in these regions are resistant to killing by radiotherapy and most anticancer drugs. Thus the combination of tirapazamine with conventional anticancer treatments is particularly effective. As of 2006, tirapazamine is undergoing phase III testing in patients with head and neck cancer and gynecological cancer, and similar trials are being undertaken for other solid tumor types. [Wikipedia]

Structure
Thumb
Synonyms
  • 1,2,4-benzotriazin-3-amine, 1,4-dioxide
  • 3-Amino-1,2,4-benzotriazine 1,4-dioxide
External IDs
SR 4233 / SR-259075 / SR-4233 / SR259075 / WIN 59075 / WIN-59075
International/Other Brands
Tirazone (Sanofi-aventis)
Categories
UNII
1UD32YR59G
CAS number
27314-97-2
Weight
Average: 178.151
Monoisotopic: 178.049075449
Chemical Formula
C7H6N4O2
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

Pharmacology

Indication

For the treatment of head and neck cancer.

Structured Indications
Not Available
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 AvailableHuman
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
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Tirapazamine.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Tirapazamine.Experimental
BevacizumabBevacizumab may increase the cardiotoxic activities of Tirapazamine.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Tirapazamine.Approved
ClotrimazoleThe metabolism of Tirapazamine can be decreased when combined with Clotrimazole.Approved, Vet Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Tirapazamine.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Tirapazamine.Experimental
Cyproterone acetateThe serum concentration of Tirapazamine can be decreased when it is combined with Cyproterone acetate.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Tirapazamine.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Tirapazamine.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Tirapazamine.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Tirapazamine.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Tirapazamine.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Tirapazamine.Experimental
IsoniazidThe metabolism of Tirapazamine can be decreased when combined with Isoniazid.Approved
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Tirapazamine.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Tirapazamine.Experimental
NicotineThe metabolism of Tirapazamine can be decreased when combined with Nicotine.Approved
OleandrinOleandrin may decrease the cardiotoxic activities of Tirapazamine.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Tirapazamine.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Tirapazamine.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Tirapazamine.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Tirapazamine.Experimental
TiclopidineThe metabolism of Tirapazamine can be decreased when combined with Ticlopidine.Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Tirapazamine.Approved, Investigational
Food Interactions
Not Available

References

General References
  1. Denny WA: Prospects for hypoxia-activated anticancer drugs. Curr Med Chem Anticancer Agents. 2004 Sep;4(5):395-9. [PubMed:15379691]
  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. [PubMed:11894020]
  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. [PubMed:3744945]
External Links
KEGG Drug
D06167
PubChem Compound
33776
PubChem Substance
175426868
ChemSpider
10437748
ChEBI
78887
ChEMBL
CHEMBL50882
Wikipedia
Tirapazamine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCervical Cancers1
1CompletedTreatmentLung Cancers2
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentUnspecified Childhood Solid Tumor, Protocol Specific1
1RecruitingTreatmentGastrointestinal Cancer Metastatic / Hepatocellular,Carcinoma / Neuroendocrine Tumors1
2CompletedTreatmentAlveolar Childhood Rhabdomyosarcoma / Embryonal Childhood Rhabdomyosarcoma / Embryonal-botryoid Childhood Rhabdomyosarcoma / Previously Treated Childhood Rhabdomyosarcoma / Recurrent Childhood Rhabdomyosarcoma1
2CompletedTreatmentCancer, Ovarian / Primary Peritoneal Cavity Cancer1
2CompletedTreatmentCervical Cancers1
2CompletedTreatmentLimited Stage Small Cell Lung Cancer1
2CompletedTreatmentSquamous Neck Carcinoma of the Head and Neck Cancer (SCCHN)1
2RecruitingTreatmentHepatocellular,Carcinoma1
3CompletedTreatmentAdenocarcinoma of the Cervix / Cervical Adenosquamous Cell Carcinoma / Cervical Squamous Cell Carcinoma / Stage IB Cervical Cancer / Stage IIA Cervical Cancer / Stage IIB Cervical Cancer / Stage III Cervical Cancer / Stage IVA Cervical Cancer1
3CompletedTreatmentHead and Neck Squamous Cell Carcinoma (HNSCC)1
3CompletedTreatmentLung Cancers2
3CompletedTreatmentNeoplasms, Head and Neck1

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
Not Available

Taxonomy

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
Aminotriazine / 1,2,4-triazine / Benzenoid / Heteroaromatic compound / Azacycle / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic amine, N-oxide, benzotriazines (CHEBI:78887)

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Unknown
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

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:7710944]

Drug created on October 18, 2007 18:36 / Updated on November 09, 2017 03:48