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MedKoo Cat#: 202980 | Name: Tretazicar
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

Tretazicar
Tretazicar
CAS#21919-05-1

Theoretical Analysis

MedKoo Cat#: 202980

Name: Tretazicar

CAS#: 21919-05-1

Chemical Formula: C9H8N4O5

Exact Mass: 252.0495

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
25mg USD 90.00 Ready to ship
50mg USD 150.00 Ready to ship
100mg USD 250.00 Ready to ship
200mg USD 450.00 Ready to ship
500mg USD 850.00 Ready to ship
1g USD 1,450.00 Ready to ship
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Related CAS #
No Data
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
More Info
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.).         

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
1: Sharrock AV, Mumm JS, Williams EM, Čėnas N, Smaill JB, Patterson AV, Ackerley DF, Bagdžiūnas G, Arcus VL. Structural Evaluation of a Nitroreductase Engineered for Improved Activation of the 5-Nitroimidazole PET Probe SN33623. Int J Mol Sci. 2024 Jun 15;25(12):6593. doi: 10.3390/ijms25126593. PMID: 38928299; PMCID: PMC11203732. 2: Day MA, Christofferson AJ, Anderson JLR, Vass SO, Evans A, Searle PF, White SA, Hyde EI. Structure and Dynamics of Three Escherichia coli NfsB Nitro- Reductase Mutants Selected for Enhanced Activity with the Cancer Prodrug CB1954. Int J Mol Sci. 2023 Mar 22;24(6):5987. doi: 10.3390/ijms24065987. PMID: 36983061; PMCID: PMC10051150. 3: Caridha D, Sciotti RJ, Sousa J, Vesely B, Teshome T, Bonkoungou G, Vuong C, Leed S, Khraiwesh M, Penn E, Kreishman-Deitrick M, Lee P, Pybus B, Lazo JS, Sharlow ER. Combination of Subtherapeutic Doses of Tretazicar and Liposomal Amphotericin B Suppresses and Cures Leishmania major-Induced Cutaneous Lesions in Murine Models. ACS Infect Dis. 2021 Feb 12;7(2):506-517. doi: 10.1021/acsinfecdis.0c00886. Epub 2021 Feb 2. PMID: 33529014. 4: Güngör T, Tokay E, Güven Gülhan Ü, Hacıoğlu N, Çelik A, Köçkar F, Ay M. Prodrugs for nitroreductase based cancer therapy-4: Towards prostate cancer targeting: Synthesis of N-heterocyclic nitro prodrugs, Ssap-NtrB enzymatic activation and anticancer evaluation. Bioorg Chem. 2020 Dec;105:104450. doi: 10.1016/j.bioorg.2020.104450. Epub 2020 Nov 4. PMID: 33189994. 5: Rich MH, Sharrock AV, Ashoorzadeh A, Patterson AV, Smaill JB, Ackerley DF. Directed evolution of the B. subtilis nitroreductase YfkO improves activation of the PET-capable probe SN33623 and CB1954 prodrug. Biotechnol Lett. 2021 Jan;43(1):203-211. doi: 10.1007/s10529-020-02992-0. Epub 2020 Aug 26. PMID: 32851465. 6: Chen SH, Sun JM, Chen BM, Lin SC, Chang HF, Collins S, Chang D, Wu SF, Lu YC, Wang W, Chen TC, Kasahara N, Wang HE, Tai CK. Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune- Competent Intracerebral Glioma Model. Int J Mol Sci. 2020 Feb 20;21(4):1433. doi: 10.3390/ijms21041433. PMID: 32093290; PMCID: PMC7073086. 7: Forterre AV, Wang JH, Delcayre A, Kim K, Green C, Pegram MD, Jeffrey SS, Matin AC. Extracellular Vesicle-Mediated In Vitro Transcribed mRNA Delivery for Treatment of HER2+ Breast Cancer Xenografts in Mice by Prodrug CB1954 without General Toxicity. Mol Cancer Ther. 2020 Mar;19(3):858-867. doi: 10.1158/1535-7163.MCT-19-0928. Epub 2020 Jan 15. PMID: 31941722; PMCID: PMC7056535. 8: Ball P, Thompson E, Anderson S, Gwenin V, Gwenin C. Time dependent HPLC analysis of the product ratio of enzymatically reduced prodrug CB1954 by a modified and immobilised nitroreductase. Eur J Pharm Sci. 2019 Jan 15;127:217-224. doi: 10.1016/j.ejps.2018.11.001. Epub 2018 Nov 8. PMID: 30414836. 9: Chan-Hyams JVE, Copp JN, Smaill JB, Patterson AV, Ackerley DF. Evaluating the abilities of diverse nitroaromatic prodrug metabolites to exit a model Gram negative vector for bacterial-directed enzyme-prodrug therapy. Biochem Pharmacol. 2018 Dec;158:192-200. doi: 10.1016/j.bcp.2018.10.020. Epub 2018 Oct 21. PMID: 30352235. 10: Devulapally R, Lee T, Barghava-Shah A, Sekar TV, Foygel K, Bachawal SV, Willmann JK, Paulmurugan R. Ultrasound-guided delivery of thymidine kinase- nitroreductase dual therapeutic genes by PEGylated-PLGA/PIE nanoparticles for enhanced triple negative breast cancer therapy. Nanomedicine (Lond). 2018 May;13(9):1051-1066. doi: 10.2217/nnm-2017-0328. Epub 2018 May 23. PMID: 29790803; PMCID: PMC6219432. 11: Gungor T, Yetis G, Onder FC, Tokay E, Tok TT, Celik A, Ay M, Kockar F. Prodrugs for Nitroreductase Based Cancer Therapy- 1: Metabolite Profile, Cell Cytotoxicity and Molecular Modeling Interactions of Nitro Benzamides with Ssap- NtrB. Med Chem. 2018;14(5):495-507. doi: 10.2174/1573406413666171129224424. PMID: 29189173. 12: Rich MH, Sharrock AV, Hall KR, Ackerley DF, MacKichan JK. Evaluation of NfsA-like nitroreductases from Neisseria meningitidis and Bartonella henselae for enzyme-prodrug therapy, targeted cellular ablation, and dinitrotoluene bioremediation. Biotechnol Lett. 2018 Feb;40(2):359-367. doi: 10.1007/s10529-017-2472-5. Epub 2017 Nov 17. PMID: 29147875. 13: Nagakubo D, Swann JB, Birmelin S, Boehm T. Autoimmunity associated with chemically induced thymic dysplasia. Int Immunol. 2017 Aug 1;29(8):385-390. doi: 10.1093/intimm/dxx048. PMID: 28992076; PMCID: PMC5890891. 14: Teng G, Ju Y, Yang Y, Hua H, Chi J, Mu X. Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro. Mol Med Rep. 2016 Dec;14(6):5164-5170. doi: 10.3892/mmr.2016.5917. Epub 2016 Nov 1. PMID: 27840931; PMCID: PMC5355654. 15: Pramanik S, Kutzner A, Heese K. 3D Structure, Dimerization Modeling, and Lead Discovery by Ligand-protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP). Mol Inform. 2016 Apr;35(3-4):99-108. doi: 10.1002/minf.201500035. Epub 2015 Jul 20. PMID: 27491919. 16: Yang Y, Lin J, Wei D. Heterologous Overexpression and Biochemical Characterization of a Nitroreductase from Gluconobacter oxydans 621H. Mol Biotechnol. 2016 Jun;58(6):428-40. doi: 10.1007/s12033-016-9942-1. PMID: 27138989. 17: Lehouritis P, Stanton M, McCarthy FO, Jeavons M, Tangney M. Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria. J Control Release. 2016 Jan 28;222:9-17. doi: 10.1016/j.jconrel.2015.11.030. Epub 2015 Dec 2. PMID: 26655063. 18: Williams EM, Little RF, Mowday AM, Rich MH, Chan-Hyams JV, Copp JN, Smaill JB, Patterson AV, Ackerley DF. Nitroreductase gene-directed enzyme prodrug therapy: insights and advances toward clinical utility. Biochem J. 2015 Oct 15;471(2):131-53. doi: 10.1042/BJ20150650. PMID: 26431849. 19: Lehouritis P, Cummins J, Stanton M, Murphy CT, McCarthy FO, Reid G, Urbaniak C, Byrne WL, Tangney M. Local bacteria affect the efficacy of chemotherapeutic drugs. Sci Rep. 2015 Sep 29;5:14554. doi: 10.1038/srep14554. PMID: 26416623; PMCID: PMC4586607. 20: Gwenin VV, Poornima P, Halliwell J, Ball P, Robinson G, Gwenin CD. Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug. Biochem Pharmacol. 2015 Dec 1;98(3):392-402. doi: 10.1016/j.bcp.2015.09.013. Epub 2015 Sep 28. PMID: 26415543.
Sharrock AV, McManaway SP, Rich MH, Mumm JS, Hermans IF, Tercel M, Pruijn FB, Ackerley DF. Engineering the Escherichia coli Nitroreductase NfsA to Create a Flexible Enzyme-Prodrug Activation System. Front Pharmacol. 2021 Jun 7;12:701456. doi: 10.3389/fphar.2021.701456. PMID: 34163368; PMCID: PMC8215503.