Tretazicar
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MedKoo CAT#: 202980

CAS#: 21919-05-1

Description: Tretazicar (CB1954) is a dinitrobenzamide prodrug that is converted in the presence of the enzyme NQO2 and co-substrate caricotamide ( EP-0152R) (EP) into a potent cytotoxic bifunctional alkylating agent. CB1954 has been proposed for use in enzyme-prodrug gene therapy systems with the Escherichia coli enzyme nitroreductase (Ntr). Ntr converts CB1954 to 2- and 4-hydroxylamino derivatives, whereupon the non-enzymatic reaction of the 4-hydroxylamino derivative with cellular thio- esters generates a potent cytotoxic bifunctional alkylating agent capable of cross-linking DNA.


Chemical Structure

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Tretazicar
CAS# 21919-05-1

Theoretical Analysis

MedKoo Cat#: 202980
Name: Tretazicar
CAS#: 21919-05-1
Chemical Formula: C9H8N4O5
Exact Mass: 252.04947
Molecular Weight: 252.18
Elemental Analysis: C, 42.86; H, 3.20; N, 22.22; O, 31.72

Price and Availability

Size Price Availability Quantity
50.0mg USD 150.0 2 Weeks
100.0mg USD 250.0 2 Weeks
200.0mg USD 450.0 2 Weeks
500.0mg USD 750.0 2 Weeks
1.0g USD 1250.0 2 Weeks
2.0g USD 2250.0 2 Weeks
5.0g USD 4950.0 2 Weeks
10.0g USD 7850.0 2 Weeks
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Synonym: CB1954; CB-1954; CB 1954; Tretazicar.

IUPAC/Chemical Name: 5-(aziridin-1-yl)-2,4-dinitrobenzamide

InChi Key: WOCXQMCIOTUMJV-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=C(N)C1=CC(N2CC2)=C([N+]([O-])=O)C=C1[N+]([O-])=O

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Preparing Stock Solutions

The following data is based on the product molecular weight 252.18 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL

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1: Prosser GA, Copp JN, Mowday AM, Guise CP, Syddall SP, Williams EM, Horvat CN, Swe PM, Ashoorzadeh A, Denny WA, Smaill JB, Patterson AV, Ackerley DF. Creation and screening of a multi-family bacterial oxidoreductase library to discover novel nitroreductases that efficiently activate the bioreductive prodrugs CB1954 and PR-104A. Biochem Pharmacol. 2013 Apr 15;85(8):1091-103. doi: 10.1016/j.bcp.2013.01.029. Epub 2013 Feb 8. PubMed PMID: 23399641.

2: Swe PM, Copp JN, Green LK, Guise CP, Mowday AM, Smaill JB, Patterson AV, Ackerley DF. Targeted mutagenesis of the Vibrio fischeri flavin reductase FRase I to improve activation of the anticancer prodrug CB1954. Biochem Pharmacol. 2012 Sep 15;84(6):775-83. doi: 10.1016/j.bcp.2012.07.002. Epub 2012 Jul 14. PubMed PMID: 22796568.

3: Prosser GA, Patterson AV, Ackerley DF. uvrB gene deletion enhances SOS chromotest sensitivity for nitroreductases that preferentially generate the 4-hydroxylamine metabolite of the anti-cancer prodrug CB1954. J Biotechnol. 2010 Oct 1;150(1):190-4. doi: 10.1016/j.jbiotec.2010.08.007. Epub 2010 Aug 19. PubMed PMID: 20727918.

4: Prosser GA, Copp JN, Syddall SP, Williams EM, Smaill JB, Wilson WR, Patterson AV, Ackerley DF. Discovery and evaluation of Escherichia coli nitroreductases that activate the anti-cancer prodrug CB1954. Biochem Pharmacol. 2010 Mar 1;79(5):678-87. doi: 10.1016/j.bcp.2009.10.008. Epub 2009 Oct 21. PubMed PMID: 19852945.

5: Jarrom D, Jaberipour M, Guise CP, Daff S, White SA, Searle PF, Hyde EI. Steady-state and stopped-flow kinetic studies of three Escherichia coli NfsB mutants with enhanced activity for the prodrug CB1954. Biochemistry. 2009 Aug 18;48(32):7665-72. doi: 10.1021/bi900674m. PubMed PMID: 19580253.

6: Vass SO, Jarrom D, Wilson WR, Hyde EI, Searle PF. E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954. Br J Cancer. 2009 Jun 16;100(12):1903-11. doi: 10.1038/sj.bjc.6605094. Epub 2009 May 19. PubMed PMID: 19455141; PubMed Central PMCID: PMC2690450.

7: Patel P, Young JG, Mautner V, Ashdown D, Bonney S, Pineda RG, Collins SI, Searle PF, Hull D, Peers E, Chester J, Wallace DM, Doherty A, Leung H, Young LS, James ND. A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. Mol Ther. 2009 Jul;17(7):1292-9. doi: 10.1038/mt.2009.80. Epub 2009 Apr 14. Erratum in: Mol Ther. 2009 Jul;17(7):1302. PubMed PMID: 19367257; PubMed Central PMCID: PMC2835198.

8: Christofferson A, Wilkie J. Mechanism of CB1954 reduction by Escherichia coli nitroreductase. Biochem Soc Trans. 2009 Apr;37(Pt 2):413-8. doi: 10.1042/BST0370413. Review. PubMed PMID: 19290872.

9: Mitchell DJ, Minchin RF. E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2. Cancer Gene Ther. 2008 Nov;15(11):758-64. doi: 10.1038/cgt.2008.47. Epub 2008 Jul 4. PubMed PMID: 18600257.

10: Chandor A, Dijols S, Ramassamy B, Frapart Y, Mansuy D, Stuehr D, Helsby N, Boucher JL. Metabolic activation of the antitumor drug 5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) by NO synthases. Chem Res Toxicol. 2008 Apr;21(4):836-43. doi: 10.1021/tx7004234. Epub 2008 Mar 28. PubMed PMID: 18370414.

11: White CL, Menghistu T, Twigger KR, Searle PF, Bhide SA, Vile RG, Melcher AA, Pandha HS, Harrington KJ. Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo. Gene Ther. 2008 Mar;15(6):424-33. Epub 2007 Dec 13. PubMed PMID: 18079753.

12: Race PR, Lovering AL, White SA, Grove JI, Searle PF, Wrighton CW, Hyde EI. Kinetic and structural characterisation of Escherichia coli nitroreductase mutants showing improved efficacy for the prodrug substrate CB1954. J Mol Biol. 2007 Apr 27;368(2):481-92. Epub 2007 Feb 11. PubMed PMID: 17350040.

13: Lukashev AN, Fuerer C, Chen MJ, Searle P, Iggo R. Late expression of nitroreductase in an oncolytic adenovirus sensitizes colon cancer cells to the prodrug CB1954. Hum Gene Ther. 2005 Dec;16(12):1473-83. PubMed PMID: 16390278.

14: AbuKhader M, Heap J, De Matteis C, Kellam B, Doughty SW, Minton N, Paoli M. Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex. J Med Chem. 2005 Dec 1;48(24):7714-9. PubMed PMID: 16302811.

15: Fu Y, Buryanovskyy L, Zhang Z. Crystal structure of quinone reductase 2 in complex with cancer prodrug CB1954. Biochem Biophys Res Commun. 2005 Oct 14;336(1):332-8. PubMed PMID: 16129418.

16: de Poorter JJ, Tolboom TC, Rabelink MJ, Pieterman E, Hoeben RC, Nelissen RG, Huizinga TW. Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954. J Gene Med. 2005 Nov;7(11):1421-8. PubMed PMID: 15977303.

17: Djeha HA, Todryk SM, Pelech S, Wrighton CJ, Irvine AS, Mountain A, Lipinski KS. Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase/CB1954 is enhanced by high-level coexpression of heat shock protein 70. Cancer Gene Ther. 2005 Jun;12(6):560-71. PubMed PMID: 15665820.

18: Felmer RN, Clark JA. The gene suicide system Ntr/CB1954 causes ablation of differentiated 3T3L1 adipocytes by apoptosis. Biol Res. 2004;37(3):449-60. PubMed PMID: 15515969.

19: Chen MJ, Green NK, Reynolds GM, Flavell JR, Mautner V, Kerr DJ, Young LS, Searle PF. Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector. Gene Ther. 2004 Jul;11(14):1126-36. PubMed PMID: 15164095.

20: Green NK, Kerr DJ, Mautner V, Harris PA, Searle PF. The nitroreductase/CB1954 enzyme-prodrug system. Methods Mol Med. 2004;90:459-77. PubMed PMID: 14657579.



Additional Information

Interim results of Clinical trials: A paper published in 2009 reproted a phase I/II clinical trial in prostate cancer (PCa) using direct intraprostatic injection of a replication defective adenovirus vector (CTL102) encoding bacterial nitroreductase (NTR) in conjunction with systemic prodrug CB1954 . One group of patients with localized PCa scheduled for radical prostatectomy received virus alone, prior to surgery, in a dose escalation to establish safety, tolerability, and NTR expression. A second group with local failure following primary treatment received virus plus prodrug to establish safety and tolerability. Based on acceptable safety data and indications of prostate-specific antigen (PSA) responses, an extended cohort received virus at a single dose level plus prodrug. The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Immunohistochemistry of resected prostate demonstrated NTR staining in tumor and glandular epithelium at all dose levels [5 x 10(10)-1 x 10(12) virus particles (vp)]. A total of 19 patients received virus plus prodrug and 14 of these had a repeat treatment; minimal toxicity was observed and there was preliminary evidence of change in PSA kinetics, with an increase in the time to 10% PSA progression in 6 out of 18 patients at 6 months. (Mol Ther. 2009 Jul;17(7):1292-9. Epub 2009 Apr 14.).