TIRAPAZAMINE

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C7H6N4O2
Molecular Weight	178.1481
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=N[N+]([O-])=C2C=CC=CC2=[N+]1[O-]

InChI

InChIKey=ORYDPOVDJJZGHQ-UHFFFAOYSA-N

InChI=1S/C7H6N4O2/c8-7-9-11(13)6-4-2-1-3-5(6)10(7)12/h1-4H,(H2,8,9)

HIDE SMILES / InChI

Molecular Formula	C7H6N4O2
Molecular Weight	178.1481
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19053884 | https://www.ncbi.nlm.nih.gov/pubmed/10606224 | https://www.ncbi.nlm.nih.gov/pubmed/1643639 | https://www.ncbi.nlm.nih.gov/pubmed/12234992 | https://www.ncbi.nlm.nih.gov/pubmed/18666379

Tumor hypoxia remains one of the greatest challenges in the treatment of solid tumors, as cancer cells in these regions are resistant to killing by radiation therapy and most anticancer drugs. Tirapazamine (3-Amino-1,2,4-benzotriazine-1,4-dioxide or SR 4233) is a cytotoxic drug with selective toxicity towards hypoxic mammalian cells. Under both aerobic and hypoxic conditions, tirapazamine is reduced by an intracellular reductase to form a highly reactive radical, which can cause DNA single- and double-strand breaks. In addition, tirapazamine under hypoxic conditions reduces the activity of topoisomerase II and stabilizes DNA topoisomerase II cleavable complexes, and these complexes remain bound to DNA. Despite the very promising results obtained in various preclinical studies and early-Phase clinical trials, several Phase III trials have failed to demonstrate any survival benefit of adding tirapazamine to chemotherapy or radiation therapy of cancers.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 282 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10606224 \| https://www.ncbi.nlm.nih.gov/pubmed/1643639	Inhibitor 8504
DNA topoisomerase II 66 Target ID: CHEMBL2094255 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12234992	Inhibitor 8504

Conditions

Condition	Modality	Highest Phase	Product
Cervical cancer 40 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24395863	Primary	Phase III 665	Unknown Approved Use Unknown
Colorectal cancer 102 Sources: http://adisinsight.springer.com/drugs/800002191	Primary	Phase II 1147	Unknown Approved Use Unknown
Hepatocellular carcinoma 83 Sources: http://adisinsight.springer.com/drugs/800002191	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
4.652 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9815534/	330 mg/m² 1 times / 3 weeks multiple, intravenous dose: 330 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TIRAPAZAMINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
7.118 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9137522	390 mg/m² 1 times / day steady-state, intravenous dose: 390 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		TIRAPAZAMINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
817.4 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9815534/	330 mg/m² 1 times / 3 weeks multiple, intravenous dose: 330 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TIRAPAZAMINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1409.8 μg × min/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9137522	390 mg/m² 1 times / day steady-state, intravenous dose: 390 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		TIRAPAZAMINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
48.7 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9815534/	330 mg/m² 1 times / 3 weeks multiple, intravenous dose: 330 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TIRAPAZAMINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
56.3 min EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9137522	390 mg/m² 1 times / day steady-state, intravenous dose: 390 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		TIRAPAZAMINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
81.3% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7781150/	unknown		TIRAPAZAMINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
450 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 450 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 450 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	DLT: deafnes, Deafness... Dose limiting toxicities: deafnes (grade 3, 100%) Deafness (grade 3, 100%) Sources: https://pubmed.ncbi.nlm.nih.gov/9815534
390 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 390 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 390 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	DLT: Deafness, Tinnitus... Dose limiting toxicities: Deafness (grade 3, 25%) Tinnitus (grade 3, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/9815534

AEs

AE	Significance	Dose	Population
Deafness	grade 3, 100% DLT	450 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 450 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 450 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/9815534
deafnes	grade 3, 100% DLT	450 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 450 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 450 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/9815534
Deafness	grade 3, 25% DLT	390 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 390 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 390 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/9815534
Tinnitus	grade 3, 25% DLT	390 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 390 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 390 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/9815534	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/9815534

Sourcing

Vendor/Aggregator	ID	URL
AChemBlock	Q65499	http://www.achemblock.com/catalogsearch/result/?q=Q65499
AK Scientific	V1806	https://aksci.com/item_detail.php?cat=V1806
Angene	AGN-PC-0O8HW1	http://www.angenechemical.com/productshow/AGN-PC-0O8HW1.html
ApexBio Technology	B3399	https://www.apexbt.com/catalogsearch/result/?q=B3399
AstaTech	T72208	http://astatechinc.com/CPSResult.php?CRNO=T72208
BOC Sciences	27314-97-2	http://www.bocsci.com/description.asp?cas=27314-97-2
Chem Scene	CS-2781	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-2781
ChemShuttle	173208	https://www.chemshuttle.com/catalogsearch/result/?q=173208
Chemspace	CSC000074987	https://chem-space.com/CSC000074987
eMolecules	260145484	https://orderbb.emolecules.com/search/#?query=260145484
eMolecules	8318945	https://orderbb.emolecules.com/search/#?query=8318945
Enamine	BBV-38275680	http://www.enaminestore.com/catalog/BBV-38275680
eNovation Chemicals	D371419	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D371419&searchbtn.x=0&searchbtn.y=0
Excenen	EX-A2967	http://www.excenen.com/searchresultlist.php?id=EX-A2967
Hairui	TISA013	http://www.hairuichem.com/en/product/search.do?q=TISA013
MedChem Express	HY-13767	https://www.medchemexpress.com/search.html?q=HY-13767&ft=&fa=&fp=
Molnova	M18344	https://www.molnova.com/en/serch-list.html?keywords=M18344
MolPort	MolPort-003-844-460	https://www.molport.com/shop/molecule-link/MolPort-003-844-460
MuseChem	I002938	https://www.musechem.com/product/I002938.html
ShangHai Biochempartner	BCP03663	http://www.biochempartner.com/search_BCP03663
TargetMol	T4434	https://www.targetmol.com/search?keyword=T4434
Tetrahedron	TS47493	http://www.thsci.com/search.do?q=TS47493
Toronto Research Chemicals	H714650	https://www.trc-canada.com/product-detail/?CatNum=H714650

PubMed

Title	Date	PubMed
Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides.	2005-06-07	15917906
Tirapazamine cytotoxicity for neuroblastoma is p53 dependent.	2005-04-01	15814660
Gateways to clinical trials.	2005-04	15834452
Tirapazamine with cisplatin and vinorelbine in patients with advanced non-small-cell lung cancer: a phase I/II study.	2005-03	15845180
Extravascular transport of drugs in tumor tissue: effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures.	2005-02-24	15715475
Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and Radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02).	2005-01-01	15625362
Improving survival and reducing toxicity with chemotherapy in advanced non-small cell lung cancer : a realistic goal?	2005	15813659
Prodrug research: futile or fertile?	2004-12-01	15498500
Gateways to clinical trials.	2004-12	15672123
[Phase II-trial of tirapazamine in combination with cisplatin and gemcitabine in patients with advanced non-small-cell-lung-cancer (NSCLC)].	2004-12	15597251
The Japanese experiences with hypoxia-targeting pharmacoradiotherapy: from hypoxic cell sensitisers to radiation-activated prodrugs.	2004-12	15571464
Enzyme-activated, hypoxia-selective DNA damage by 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide.	2004-11	15540937
Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo.	2004-10-18	15467770
Gateways to clinical trials.	2004-10	15605126
Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia.	2004-09-13	15305198
Prospects for hypoxia-activated anticancer drugs.	2004-09	15379691
Cytochrome P450 CYP1B1 activity in renal cell carcinoma.	2004-08-31	15280921
Phase I study of tirapazamine plus cisplatin/etoposide and concurrent thoracic radiotherapy in limited-stage small cell lung cancer (S0004): a Southwest Oncology Group study.	2004-08-15	15328179
Phosphorylated histone H2AX in spheroids, tumors, and tissues of mice exposed to etoposide and 3-amino-1,2,4-benzotriazine-1,3-dioxide.	2004-08-01	15289343
Enhanced effectiveness of radiochemotherapy with tirapazamine by local application of electric pulses to tumors.	2004-08	15387146
Clinical studies of hypoxia modification in radiotherapy.	2004-07	15254866
Oxidation of 2-deoxyribose by benzotriazinyl radicals of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides.	2004-06-30	15212534
Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors.	2004-06	15161354
1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part III.	2004-05	15095420
1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part II.	2004-05	15095418
New derivatives of quinazoline and 1, 2-dihydroquinazoline n3-oxide with expected antitumor activity.	2004-05	15095417
Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study.	2004-04-15	15084615
Gateways to clinical trials.	2004-04	15148527
2-Amino metabolites are key mediators of CB 1954 and SN 23862 bystander effects in nitroreductase GDEPT.	2004-03-08	14997211
Gateways to clinical trials.	2004-03	15071612
Enzyme-catalyzed activation of anticancer prodrugs.	2004-03	15001663
Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting cure.	2004-02-15	14973055
Selective potentiation of the hypoxic cytotoxicity of tirapazamine by its 1-N-oxide metabolite SR 4317.	2004-01-15	14744792
DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: potent analogues of the hypoxia-selective cytotoxin tirapazamine.	2004-01-15	14711317
The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines.	2004-01	15090746
Antiangiogenic hypoxic cytotoxin TX-402 inhibits hypoxia-inducible factor 1 signaling pathway.	2003-12-12	14666730
Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro.	2003-12-01	14647149
Endogenous markers of tumor hypoxia predictors of clinical radiation resistance?	2003-12	14652668
NLCQ-1 (NSC 709257): exploiting hypoxia with a weak DNA-intercalating bioreductive drug.	2003-11-15	14654556
Enhanced conversion of DNA radical damage to double strand breaks by 1,2,4-benzotriazine 1,4-dioxides linked to a DNA binder compared to tirapazamine.	2003-11	14615975
The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models.	2003-10-20	14562035
Human NADPH-cytochrome p450 reductase overexpression does not enhance the aerobic cytotoxicity of doxorubicin in human breast cancer cell lines.	2003-10-15	14583491
Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.	2003-10-01	14555506
DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine).	2003-09-24	13129365
Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures.	2003-09-15	14522924
Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK.	2003-08-04	12888809
Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks.	2003-08-01	12907603
Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies.	2003-08	12927570
A simple method of producing low oxygen conditions with oxyrase for cultured cells exposed to radiation and tirapazamine.	2003-08	12902904
A mass spectrometry study of tirapazamine and its metabolites. insights into the mechanism of metabolic transformations and the characterization of reaction intermediates.	2003-08	12892912

Patents

Sample Use Guides

In Vivo Use Guide

Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used tirapazamine (TPZ) 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ.

Route of Administration: Intravenous

In Vitro Use Guide

Tirapazamine-treated V79 Chinese hamster cells were tested for cytotoxicity by colony assay and growth inhibition by the MTT assay. The survival of V79 cells after being exposed to 100 microM of tirapazamine for 2 h was about 78% of untreated controls. The mitotic cell counts of V79 cells approached zero after 4 h treatment of tirapazamine at 100 microM or 3 h at 300 microM. The fragmentation pattern of DNA isolated from cells 2 h after 300 microM tirapazamine treatment showed characteristics of apoptotic cells.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:05:50 GMT 2025` Edited by `admin` on `Mon Mar 31 18:05:50 GMT 2025`
Record UNII	1UD32YR59G
Record Status	`Validated (UNII)`
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Name

Type

Language

NSC-130181

Preferred Name

English

TIRAPAZAMINE

Official Name

English

tirapazamine [INN]

Common Name

English

SML-0552

Code

English

SML0552

Code

English

3-Amino-1,2,4-benzotriazine 1,4-dioxide

Systematic Name

English

Tirapazamine [WHO-DD]

Common Name

English

WIN-59075

Code

English

TIRAPAZAMINE [USAN]

Common Name

English

SR259075

Code

English

WIN59075

Code

English

1,2,4-BENZOTRIAZIN-3-AMINE, 1,4-DIOXIDE

Systematic Name

English

SR4233

Code

English

Tirazone

Common Name

English

TIRAPAZAMINE [MI]

Common Name

English

SR-259075

Code

English

SR-4233

Code

English

TIRAPAZAMINE [MART.]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/17/1897