27314-97-2

Usage

Uses

Used in Anticancer Applications:
3-AMINO-1,2,4-BENZOTRIAZINE-1,4-DIOXIDE is used as a bioreductive anticancer agent for its selective toxicity to cells under hypoxic conditions. It functions as an antineoplastic, contributing to the fight against cancer.
Used in Cytotoxicity Studies:
In the field of cancer research, 3-AMINO-1,2,4-BENZOTRIAZINE-1,4-DIOXIDE is used to evaluate its cytotoxic effect on various cancer cell lines, such as U-251 MG (glioblastoma cell line), DT40 cells, HT-1080, and A549 cells. Its application aids in understanding its potential role in cancer treatment and its effects on cell viability under hypoxic conditions.
Used in Drug Sensitization:
3-AMINO-1,2,4-BENZOTRIAZINE-1,4-DIOXIDE is utilized to sensitize tumors to other cancer treatments, such as cisplatin in a mouse RIF-1 fibrosarcoma tumor model and fractionated irradiation in a FaDu hypopharyngeal squamous cell carcinoma mouse xenograft model. This application highlights its potential to enhance the effectiveness of existing cancer therapies.
Used in Pharmaceutical Industry:
3-AMINO-1,2,4-BENZOTRIAZINE-1,4-DIOXIDE is used as an active pharmaceutical ingredient for the development of new drugs targeting cancer. Its unique properties and potential applications make it a valuable compound in the search for novel anticancer treatments.
Used in Chemical Research:
In the chemical research industry, 3-AMINO-1,2,4-BENZOTRIAZINE-1,4-DIOXIDE serves as a key compound for studying its chemical properties, reactivity, and potential applications in various chemical processes and reactions.

Biochem/physiol Actions

Under hypoxic conditions, tirapazamine is a potent cytotoxic agent that induces apoptosis by inducing breaks in single and double stranded DNA, as well as chromosomal breaks. The compound sensitizes cells to other ionizing radiation and other cytotoxic agents like cisplatin.

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

Upstream product

• 20028-80-2 SR 4330 
• 5424-06-6 3-amino-1,2,4-benzotriazine 1-oxide 
• 480-96-6 benzofurazan oxide 
• 420-04-2 CYANAMID 
• 112970-44-2 2-bromo-3-methoxyaniline 
• 27446-08-8 3-oxo-3,4-dihydrobenzo-1,2,4-triazine 1-oxide 
• 67692-91-5 3-chloro-1,2,4-benzotriazine 1-oxide 
• 528-29-0 1,2-Dinitrobenzene 
• 1493-27-2 ortho-nitrofluorobenzene 
• 88-74-4 2-nitro-aniline 
• 20028-79-9 3-CH₃CONH-1,2,4-benzotriazine-1-oxide 

Downstream Products

• 5424-06-6 3-amino-1,2,4-benzotriazine 1-oxide 
• 34371-14-7 2-deoxy-D-ribonolactone 
• 59399-05-2 phenylacetic acid 3-imino-1-oxy-3H-benzo[1,2,4]triazin-4-yl ester 
• 59399-06-3 7-methoxy-1-oxy-4-propionyloxy-4H-benzo[e][1,2,4]triazin-3-ylideneamine 
• 39132-82-6 2H-<1,2,4>oxadiazolo<3,2-c><1,2,4>benzotriazin-2-one-5-oxide 
• 27315-02-2 3-acetylamino-1,2,4-benzotriazine-1,4-dioxide 
• 121135-31-7 1,2,4-benzotriazine-1,4-dioxide 
• 59399-03-0 4-benzoyloxy-1-oxy-4H-benzo[1,2,4]triazin-3-ylideneamine 
• 59399-02-9 4-acetoxy-1-oxy-4H-benzo[1,2,4]triazin-3-ylideneamine 
• 20028-80-2 SR 4330 
• 251322-95-9 3-amino-1,2,4-benzotriazine 4-oxide 

Relevant academic research and scientific papers

A redox-activatable biopolymer-based micelle for sequentially enhanced mitochondria-targeted photodynamic therapy and hypoxia-dependent chemotherapy

A tumor redox-activatable micellar nanoplatform based on the naturally occurring biomacromolecule hyaluronic acid (HA) was developed for complementary photodynamic/chemotherapy against CD44-positive tumors. Here HA was first conjugated with l-carnitine (Lc)-modified zinc phthalocyanine (ZnPc) via disulfide linkage and then co-assembled with tirapazamine (TPZ) to afford the physiologically stable micellar nanostructure. The mitochondria-targeted photodynamic activity of ZnPc-Lc could efficiently activate the mitochondrial apoptosis cascade and deplete the oxygen in the tumor intracellular environment to amplify the hypoxia-dependent cytotoxic effect of TPZ.

A convenient synthesis of 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR 4233) and related compounds via nucleophilic aromatic substitution between nitroarenes and guanidine base

Reaction of 1-fluoro-2-nitrobenzene or 1,2-dinitrobenzene with guanidine in hot THF followed by treatment with potassium tert-butoxide gave 3-amino-1,2,4-benzotriazine 1-oxide in good yield, which was further oxidized by peracetic acid to afford the title compound.

Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline

Monoxide and dioxide of animo quinoxaline were synthesized and characterized by 1H NMR, 13C NMR and HRMS. The result shows that monoxide is main product. 1H NMR analysis, quantum calculation and crystal structure all indicate that the monoxide is 4-oxide structure but not 1-oxide structure. The subsequent discussions of electronic effect and steric effect of 1-oxide and 4-oxide support the conclusion that 4-oxide is dominant product, which is consistent with 1H NMR analysis and crystal structure. At last, the calculated structure is in good agreement with the crystal structure in this paper, which indicates that the calculation result in this paper is credible.

Tirapazamine drug carrier with core-shell structure, and preparation method and application thereof

The invention relates to a tirapazamine drug carrier with a core-shell structure, and a preparation method and an application thereof, belonging to the technical field of drug preparation. According to the invention, hyaluronic acid, dithiodiacetic acid, tetraamino zinc phthalocyanine and L-carnitine are connected through a chemical action to form the tirapazamine drug carrier with the core-shellstructure, wherein a tetraamino zinc phthalocyanine-L-carnitine part is a core; a hyaluronic acid-dithiodiacetic acid part is a shell; the hyaluronic acid and the L-carnitine are used for improving the hydrophobicity of the tetramino zinc phthalocyanine; and a carrier micelle with hydrophilicity and cell-membrane and mitochondrion double-targeting effects is formed. A tirapazamine drug (TPZ) is loaded into the carrier to form a tirapazamine drug-loaded micelle with a core-shell structure, and oxygen is consumed through photodynamic treatment to activate the tirapazamine drug (TPZ), so a photodynamic and chemotherapy synergistic therapy is realized; the drug resistance of chemotherapy and the resistance of cells to photodynamic are avoided; and good application prospects are realized in preparation of anti-tumor drugs.

Exploiting the Inherent Photophysical Properties of the Major Tirapazamine Metabolite in the Development of Profluorescent Substrates for Enzymes That Catalyze the Bioreductive Activation of Hypoxia-Selective Anticancer Prodrugs

Hypoxia-selective cytotoxins (HSCs) seek to exploit the oxygen-poor nature of tumor tissue for therapeutic gain. Typically, HSCs require activation by one-electron bioreductive enzymes such as NADPH:cytochrome P450 reductase (CYPOR). Thus, successful clinical deployment of HSCs may be facilitated by the development and implementation of diagnostic probes that detect the presence of relevant bioreductive enzymes in tumor tissue. The work described here develops analogues of the well-studied HSC tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, TPZ) as profluorescent substrates of the one-electron reductases involved in bioactivation of HSCs. Hypoxic metabolism of TPZ or 7-fluoro-TPZ by one-electron reductases releases inherently fluorescent mono-N-oxide metabolites that may serve as indicators, probes, markers, or stains for the detection of the enzymes involved in the bioactivation of HSCs. In particular, profluorescent compounds of this type can provide a foundation for fluorescence-based bioassays that help identify tumors responsive to HSCs.

3 - Amido - 1, 2, 4 - benzene and three qinqin kinds in use in the preparation of a tumor sensitizer

The invention relates to compounds which have a general formula (I), and pharmaceutically acceptable medicinal salt of the compounds which have the general formula (I), wherein R is defined in the specifications. The invention also discloses a preparation method for 3-acylamino-1,2,4-phentriazine derivatives, and a sensibilization effect of the 3-acylamino-1,2,4-phentriazine derivatives in the radiotherapy and chemotherapy of tumor.

Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives

A new efficient total synthesis of the phenazine 5,10-dioxide natural products iodinin and myxin and new compounds derived from them was achieved in few steps, a key-step being 1,6-dihydroxyphenazine di-N-oxidation. Analogues prepared from iodinin, including myxin and 2-ethoxy-2-oxoethoxy derivatives, had fully retained cytotoxic effect against human cancer cells (MOLM-13 leukemia) at atmospheric and low oxygen level. Moreover, iodinin was for the first time shown to be hypoxia selective. The structure-activity relationship for leukemia cell death induction revealed that the level of N-oxide functionality was essential for cytotoxicity. It also revealed that only one of the two phenolic functions is required for activity, allowing the other one to be modified without loss of potency.

Transferring oxygen isotopes to 1,2,4-benzotriazine 1-oxides forming the corresponding 1,4-dioxides by using the HOF·CH3CN complex

Heterocyclic benzotriazine N-oxides are an interesting class of experimental anticancer and antibacterial agents. Analogs with 18O incorporated into the N-oxide group may offer useful mechanistic tools. We describe the use of H218OF·CH3CN in a fast, readily executed and high-yielding preparation of 1,2,4-benzotriazine 1,4-dioxides containing an 18O-label at the 4-oxide position.

Complete 1H, 13C and 15N NMR assignment of tirapazamine and related 1,2,4-benzotriazine N-oxides

1H, 13C and 15N NMR measurements (1D and 2D including 1H-15N gs-HMBC) have been carried out on 3-amino-1, 2,4-benzotriazine and a series of N-oxides and complete assignments established. N-Oxidation at any position resulted in large upfield shifts of the corresponding N-1 and N-2 resonances and downfield shifts for N-4 with the exception of the 3-amino-1,2,4-benzotriazine 1-oxide in which a small upfield shift of N-4 was observed. Density functional GIAO calculations of the 15N and 13C chemical shifts [B3LYP/6-31G(d)//B3LYP/6- 311+G(2d,p)] gave good agreement with experimental values confirming the assignments. The combination of 13C and 15N NMR provides an unambiguous method for assigning the 1H and 13C resonances of N-oxides of 1,2,4-benzotriazines. Copyright

Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxidest

Revealing the free radical mechanism by which the anticancer drug tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) induces hypoxia-selective cytotoxicity, is seen as a way forward to develop clinically useful bioreductive drugs against chemo- and radiation-resistant hypoxic tumor cells. Our previous studies point to the formation of an active benzotriazinyl radical following the one-electron reduction of tirapazamine and its elimination of water from the initial reduction intermediate, and have suggested that this species is a cytotoxin. In this paper we have used pulse radiolysis to measure the one-electron reduction potentials of the benzotriazinyl radicals E(B ?,H+/B) of 30 analogues of tirapazamine as well as the one-electron reduction potentials of their two-electron reduced metabolites, benzotriazine 1-oxides E(B/B?-. The redox dependencies of the back-oxidation of the one-electron reduced benzotriazine 1,4-dioxides by oxygen, their radical prototropic properties and water elimination reactions were found to be tracked in the main by the one-electron reduction potentials of the benzotriazine 1,4-dioxides E(A/A?-). Multiple regression analysis of published aerobic and hypoxic clonogenic cytotoxicity data for the SCCVII murine tumor cell line with the physical chemistry parameters measured in this study, revealed that hypoxic cytotoxicity is dependent on E(B ?, H-/B) thus providing strong evidence that the benzotriazinyl radicals are the active cytotoxic species in hypoxia, while aerobic cytotoxicity is dependent on E(B/B?-). It is concluded that maximizing the differential ratio between these two controlling parameters, in combination with necessary pharmacological aspects, will lead to more efficacious anticancer bioreductive drugs. The Royal Society of Chemistry 2005.