TRETAZICAR

Details

Stereochemistry	ACHIRAL
Molecular Formula	C9H8N4O5
Molecular Weight	252.1836
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=O)C1=CC(N2CC2)=C(C=C1[N+]([O-])=O)[N+]([O-])=O

InChI

InChIKey=WOCXQMCIOTUMJV-UHFFFAOYSA-N

InChI=1S/C9H8N4O5/c10-9(14)5-3-7(11-1-2-11)8(13(17)18)4-6(5)12(15)16/h3-4H,1-2H2,(H2,10,14)

HIDE SMILES / InChI

Description
Sources: https://adisinsight.springer.com/drugs/800019051 | https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/08/529-public-summary-positive-opinion-orphan-designation-tretazicar-treatment-visceral-leishmaniasis_en.pdf | https://ascopubs.org/doi/abs/10.1200/jco.2008.26.15_suppl.2505

Tretazicar is a dinitrobenzamide prodrug that is converted in the presence of the enzyme NQO2 and co-substrate caricotamide (EP-0152R) into a potent cytotoxic bifunctional alkylating agent. Tretazicar is a product that belongs to a family of products used in the treatment of cancer because of its capacity to kill cells. The enzyme that activates tretazicar is present in leishmania cells where the product can be transformed and be active. Tretazicar kills infected cells by binding to the genetic material (DNA) of the cells and creating bonds that disrupt the genetic material and its function, finally resulting in the death of the infected cell. On 4 February 2008, orphan designation EU/3/08/529 was granted by the European Commission to Morvus Technology Limited, United Kingdom, for tretazicar for the treatment of visceral leishmaniasis. On 4 February 2008, orphan designation EU/3/08/529 was granted by the European Commission to Morvus Technology Limited, United Kingdom, for tretazicar for the treatment of visceral leishmaniasis. Tretazicar had been in phase II clinical trial for the treatment of liver cancer. However, this development was discontinued.

Originator

Approval Year

PubMed

Title	Date	PubMed
Clostridia in cancer therapy.	2003 Dec	15035028
The gene suicide system Ntr/CB1954 causes ablation of differentiated 3T3L1 adipocytes by apoptosis.	2004	15515969
Quinone reductase-mediated nitro-reduction: clinical applications.	2004	15047103
The nitroreductase/CB1954 enzyme-prodrug system.	2004	14657579
Methods to improve efficacy in suicide gene therapy approaches: targeting prodrug-activating enzymes carboxypeptidase G2 and nitroreductase to different subcellular compartments.	2004	14657569
Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector.	2004 Jul	15164095
Aziridinyldinitrobenzamides: synthesis and structure-activity relationships for activation by E. coli nitroreductase.	2004 Jun 3	15163209
Enzyme-catalyzed activation of anticancer prodrugs.	2004 Mar	15001663
2-Amino metabolites are key mediators of CB 1954 and SN 23862 bystander effects in nitroreductase GDEPT.	2004 Mar 8	14997211
Genes in the service of therapeutic index: progress for virus-directed enzyme prodrug therapy.	2004 May 1	15051753
Nitroreductase: a prodrug-activating enzyme for cancer gene therapy.	2004 Nov	15566399
Inhibition of NF-kappaB enhances the cytotoxicity of virus-directed enzyme prodrug therapy and oncolytic adenovirus cancer gene therapy.	2005 Aug	15800660
Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex.	2005 Dec 1	16302811
Aerobic 2- and 4-nitroreduction of CB 1954 by human liver.	2005 Dec 15	16129536
Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase/CB1954 is enhanced by high-level coexpression of heat shock protein 70.	2005 Jun	15665820
Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954.	2005 Nov	15977303
Crystal structure of quinone reductase 2 in complex with cancer prodrug CB1954.	2005 Oct 14	16129418
Delivery of the bacterial nitroreductase gene into endothelial cells prolongs the survival of tumour-bearing mice by bystander mechanisms.	2006 Feb	16391801
New enzyme for reductive cancer chemotherapy, YieF, and its improvement by directed evolution.	2006 Jan	16432167
Hypoxia: targeting the tumour.	2006 Jul	16842231
Design, synthesis, and biological evaluation of cyclic and acyclic nitrobenzylphosphoramide mustards for E. coli nitroreductase activation.	2006 Jul 13	16821793
Nitroreductase-based therapy of prostate cancer, enhanced by raising expression of heat shock protein 70, acts through increased anti-tumour immunity.	2006 Mar	16075195
Reduction of mitomycin C is catalysed by human recombinant NRH:quinone oxidoreductase 2 using reduced nicotinamide adenine dinucleotide as an electron donating co-factor.	2006 Nov 6	17031400
Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo.	2006 Nov 6	17024128
Application of a microfluidic reactor for screening cancer prodrug activation using silica-immobilized nitrobenzene nitroreductase.	2006 Sep	16961327
Direct positive selection for improved nitroreductase variants using SOS triggering of bacteriophage lambda lytic cycle.	2007 Apr	17301844
Kinetic and structural characterisation of Escherichia coli nitroreductase mutants showing improved efficacy for the prodrug substrate CB1954.	2007 Apr 27	17350040
The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411(NTR).	2007 Dec	17975564
Validation of nitroreductase, a prodrug-activating enzyme, mediated cell death in embryonic zebrafish (Danio rerio).	2007 Jun	17605338
Gateways to clinical trials.	2007 Mar	17440629
NAD(P)H:quinone oxidoreductase 1 and nrh:quinone oxidoreductase 2 activity and expression in bladder and ovarian cancer and lower NRH:quinone oxidoreductase 2 activity associated with an NQO2 exon 3 single-nucleotide polymorphism.	2007 Mar 1	17332305
Ablation of central nervous system progenitor cells in transgenic rats using bacterial nitroreductase system.	2007 May 1	17304579
Hepatic nitroreduction, toxicity and toxicokinetics of the anti-tumour prodrug CB 1954 in mouse and rat.	2007 Oct 30	17804142
Combining gene and immunotherapy for prostate cancer.	2008	17726452
Metabolic activation of the antitumor drug 5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) by NO synthases.	2008 Apr	18370414
SALMON: solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy.	2008 Jan 10	18062662
Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo.	2008 Mar	18079753
E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2.	2008 Nov	18600257
The NprA nitroreductase required for 2,4-dinitrophenol reduction in Rhodobacter capsulatus is a dihydropteridine reductase.	2008 Nov	18355323
Optimized clostridium-directed enzyme prodrug therapy improves the antitumor activity of the novel DNA cross-linking agent PR-104.	2008 Oct 1	18829557
Steady-state and stopped-flow kinetic studies of three Escherichia coli NfsB mutants with enhanced activity for the prodrug CB1954.	2009 Aug 18	19580253
A mammalianized synthetic nitroreductase gene for high-level expression.	2009 Aug 27	19712451
A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984].	2009 Jul	19367257
Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy.	2009 Jun	19528476
E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954.	2009 Jun 16	19455141
A new in vitro model for stem cell differentiation and interaction.	2009 Mar	19383416
Antivector and tumor immune responses following adenovirus-directed enzyme prodrug therapy for the treatment of prostate cancer.	2009 Nov	19619056
Bystander or no bystander for gene directed enzyme prodrug therapy.	2009 Nov 10	19924084
Quinone oxidoreductase-2-mediated prodrug cancer therapy.	2010 Jul 14	20630857
Transgenic mice expressing nitroreductase gene under the control of the podocin promoter: a new murine model of inductible glomerular injury.	2010 Mar	19806361

Name

Type

Language

TRETAZICAR

Official Name

English

5-(AZIRIDIN-1-YL)-2,4-DINITROBENZAMIDE

Systematic Name

English

NSC-115829

Code

English

CB-1954

Code

English

tretazicar [INN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/08/529