- A redox-activatable biopolymer-based micelle for sequentially enhanced mitochondria-targeted photodynamic therapy and hypoxia-dependent chemotherapy
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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.
- Fei, Yang,Hou, Yanhua,Hu, Yan,Li, Menghuan,Li, Yanan,Luo, Zhong,Sutrisno, Linawati,Xue, Chengcheng
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- 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
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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.
- Suzuki, Hitomi,Kawakami, Takehiko
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- Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline
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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.
- Li, Junjian,Wang, Rui,Wang, Wenfeng,Wang, Xucheng,Yuan, Yaofeng,Zhang, Min
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- Tirapazamine drug carrier with core-shell structure, and preparation method and application thereof
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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.
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Paragraph 0074; 0080
(2020/06/02)
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- 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
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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.
- Shen, Xiulong,Laber, Charles H.,Sarkar, Ujjal,Galazzi, Fabio,Johnson, Kevin M.,Mahieu, Nathaniel G.,Hillebrand, Roman,Fuchs-Knotts, Tarra,Barnes, Charles L.,Baker, Gary A.,Gates, Kent S.
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p. 3126 - 3131
(2018/03/23)
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- 3 - Amido - 1, 2, 4 - benzene and three qinqin kinds in use in the preparation of a tumor sensitizer
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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.
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Paragraph 0041-0043
(2018/04/20)
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- Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives
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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.
- Viktorsson, Elvar ?rn,Melling Gr?the, Bendik,Aesoy, Reidun,Sabir, Misbah,Snellingen, Simen,Prandina, Anthony,H?gmoen ?strand, Ove Alexander,Bonge-Hansen, Tore,D?skeland, Stein Ove,Herfindal, Lars,Rongved, P?l
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supporting information
p. 2285 - 2293
(2017/03/24)
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- Transferring oxygen isotopes to 1,2,4-benzotriazine 1-oxides forming the corresponding 1,4-dioxides by using the HOF·CH3CN complex
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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.
- Gatenyo, Julia,Johnson, Kevin,Rajapakse, Anuruddha,Gates, Kent S.,Rozen, Shlomo
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p. 8942 - 8944
(2012/10/29)
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- Complete 1H, 13C and 15N NMR assignment of tirapazamine and related 1,2,4-benzotriazine N-oxides
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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
- Boyd, Maruta,Hay, Michael P.,Boyd, Peter D. W.
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p. 948 - 954
(2008/02/03)
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- Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxidest
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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.
- Anderson, Robert F.,Shinde, Sujata S.,Hay, Michael P.,Gamage, Swarna A.,Denny, William A.
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p. 2167 - 2174
(2007/10/03)
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- 3-amino-1,2,4-benzotriazine 4-oxide: Characterization of a new metabolite arising from bioreductive processing of the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)
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Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not been completely characterized. The two previously characterized metabolites are 3-amino-1,2,4-benzotriazine 1-oxide (3) and 3-amino-1,2,4-benzotriazine (5). In this work, 3-amino-1,2,4-benzotriazine 4-oxide (4) is identified for the first time as a product resulting from one-electron activation of the antitumor agent tirapazamine by the enzymes xanthine/xanthine oxidase and NADPH:cytochrome P450 oxidoreductase. As part of this work, the novel N-oxide (4) was unambiguously synthesized and characterized using NMR spectroscopy, UV-vis spectroscopy, LC/MS, and X-ray crystallography. Under conditions where the parent drug tirapazamine is enzymatically activated, the metabolite 4 is produced but readily undergoes further reduction to the benzotriazine (5). Thus, under circumstances where extensive reductive metabolism occurs, the yield of the 4-oxide (4) decreases. In contrast, the isomeric two-electron reduction product 3-amino-1,2,4-benzotriazine 1-oxide (3) does not readily undergo enzymatic reduction and, therefore, is found as a major bioreductive metabolite under all conditions. Finally, the ability of the 4-oxide metabolite (4) to participate in tirapazamine-mediated DNA damage is considered.
- Fuchs,Chowdhury,Barnes,Gates
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p. 107 - 114
(2007/10/03)
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- Process for preparing 1,2,4-benzotriazine oxides
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A method of using 1,2,4-benzotriazine oxides, some of which are novel compounds, as radiosensitizers and selective cytotoxic agents is disclosed. These compounds are shown to specifically radiosensitize hypoxic tumor cells. Some are additionally disclosed to be useful as specific cytotoxic agents for these cells. They also show an unexpected ability to radiosensitize aerobic cells following or preceding a hypoxic incubation of the cells with the drug. This provides a basis for selective radiosensitization of tumors compared to normal cells. A novel method for preparing the 1,2,4-benzotriazine oxides is also disclosed.
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- 3-Amino-1,2,4-benzotriazine-1,4-di-N-oxide compositions and method of using same
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Pharmaceutical compositions comprising a 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide as the active ingredient and method of using same. Said compositions exhibit antimicrobial activity and may be used to promote livestock growth by adding an effective amount of said composition to edible fodder.
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