5424-06-6Relevant articles and documents
Putative electron-affinic radiosensitizers and markers of hypoxic tissue: Synthesis and preliminary in vitro biological characterization of C3-amino-substituted benzotriazine dioxides (BTDOs)
Elsaidi, Hassan RH.,Yang, Xiao-Hong,Ahmadi, Fatemeh,Weinfeld, Michael,Wiebe, Leonard I.,Kumar, Piyush
, p. 216 - 224 (2019)
Introduction: The redox characteristics of 1,2,4-benzotriazine-1,4-dioxides (BTDOs) make them potential radiosensitizing agents for hypoxic cells in solid human cancers. Tirapazamine (TPZ) is the most clinically tested BTDO radiosensitizer, despite its toxicity at effective doses. To date, no BTDOs have been developed as diagnostic markers of tissue hypoxia. Hypothesis: TPZ analogues with appropriate reporting groups can act as potential radiosensitizers and hypoxia selective diagnostics. Experimental and results: 3-Chloro-1,2,4-benzotriazine 1-oxide was substituted at the C3 position to afford 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide, which was oxidized to 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (HO-EOE-TPZ) or converted to 3-(2-tosyloxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (Tos-EOE-TPZ). Tos-EOE-TPZ was intended for use as a synthon for preparing 3-(2-azidoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (N3-EOE-TPZ) and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ). The logP values (?0.69 to 0.61) for these molecules bracketed that of TPZ (?0.34). Cell line dependent cytotoxicities (IC50) in air were in the 10–100 μM range, with Hypoxia Cytotoxicity Ratios (HCR; IC50-air/IC50-hypoxia) of 5–10. LUMO calculations indicated that these molecules are in the optimal redox range for radiosensitization, offering cell-line-specific Relative Radiosensitization Ratios (RRSR; SER/OER) of 0.58–0.88, compared to TPZ (0.67–0.76). Conclusion: The LUMO, IC50, HCR and RRSR values of 3-(2-substituted ethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxides are similar to the corresponding values for TPZ, supporting the conclusion that these TPZ analogues are potentially useful as hypoxia-activated radiosensitizers. Further studies into their biodistributions in animal models are being pursued to determine the in vivo potential in hypoxia management.
Toward hypoxia-selective DNA-alkylating agents built by grafting nitrogen mustards onto the bioreductively activated, hypoxia-selective DNA-oxidizing agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)
Johnson, Kevin M.,Parsons, Zachary D.,Barnes, Charles L.,Gates, Kent S.
, p. 7520 - 7531 (2014)
Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells.
ORGANIC COMPOUND AND ORGANIC ELECTROLUMINESCENT DEVICE USING THE SAME
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Paragraph 0180-0183, (2021/07/06)
The present invention relates to a novel organic compound and an organic electroluminescent device using the same. An organic electroluminescent device is provided to improve luminous efficiency, driving voltage and lifetime by including an organic compound having excellent luminous efficiency, electron transporting capability, electrochemical stability, and thermal stability.
Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline
Li, Junjian,Wang, Rui,Wang, Wenfeng,Wang, Xucheng,Yuan, Yaofeng,Zhang, Min
, (2020/07/27)
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
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Paragraph 0074; 0077-0079, (2020/06/02)
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.
A redox-activatable biopolymer-based micelle for sequentially enhanced mitochondria-targeted photodynamic therapy and hypoxia-dependent chemotherapy
Fei, Yang,Hou, Yanhua,Hu, Yan,Li, Menghuan,Li, Yanan,Luo, Zhong,Sutrisno, Linawati,Xue, Chengcheng
supporting information, p. 9978 - 9981 (2020/09/23)
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.
3-Substituted Benzo[ e][1,2,4]triazines: Synthesis and Electronic Effects of the C(3) Substituent
Bodzioch, Agnieszka,Pomik?o, Dominika,Celeda, Ma?gorzata,Pietrzak, Anna,Kaszyński, Piotr
, p. 6377 - 6394 (2019/05/24)
A series of 19 structurally diverse C(3)-substituted derivatives of benzo[e][1,2,4]triazine were synthesized from 3-chloro- (1c) and 3-iodobenzo[e][1,2,4]triazine (1d) obtained in three steps from 2-nitroaniline in 37-55% yields. Nucleophilic aromatic substitution and metal-catalyzed (Pd, Cu) reactions led to functional derivatives that include alkyl (C5H11), (het)aryl (Ph, 2-thienyl, ferrocenyl), ArCC, amine (NHPh and morpholine), PO(OEt)2, sulfanyl (SBu-t), alkoxide (OEt, OMe), and CN. The synthesis of C(3)-CF3 derivative 1g via the Ruppert reaction with 1d and its 1-oxide analogue 2d led to the substitution followed by formal addition of HCF3 to the C?N bond. Pd-catalyzed carbonylation reactions of 1d and 2d did not give the corresponding C(3)-carboxylic acids. Therefore, acid 1f was obtained through hydrolysis of the CN. The substituent effect on the electronic structure of the benzo[e][1,2,4]triazine ring was investigated by spectroscopic methods (UV-vis and NMR) augmented with density functional theory calculations. Results show significant effect of the C(3) substituent on the (1) transition energy and good correlation of the 1H NMR chemical shift with the substituent constant σp. Molecular and crystal structures of six derivatives were established with the single-crystal X-ray diffraction method, and the substituent impact on the molecular geometry was investigated.
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
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.
, p. 3126 - 3131 (2018/03/23)
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.
Application of Suzuki–Miyaura and Buchwald–Hartwig Cross-coupling Reactions to the Preparation of Substituted 1,2,4-Benzotriazine 1-Oxides Related to the Antitumor Agent Tirapazamine
Sarkar, Ujjal,Hillebrand, Roman,Johnson, Kevin M.,Cummings, Andrea H.,Phung, Ngoc Linh,Rajapakse, Anuruddha,Zhou, Haiying,Willis, Jordan R.,Barnes, Charles L.,Gates, Kent S.
, p. 155 - 160 (2017/02/05)
Many 1,2,4-benzotriazine 1,4-dioxides display the ability to selectively kill the oxygen-poor cells found in solid tumors. As a result, there is a desire for synthetic routes that afford access to substituted 1,2,4-benzotriazine 1-oxides that can be used as direct precursors in the synthesis of 1,2,4-benzotriazine 1,4-dioxides. Here we describe the use of Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions for the construction of various 1,2,4-benzotriazine 1-oxide analogs bearing substituents at the 3-position, 6-position, and 7-position.
Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4- benzotriazine-1,4-dioxide derivatives
Xia, Qing,Zhang, Ling,Zhang, Jun,Sheng, Rong,Yang, Bo,He, Qiaojun,Hu, Yongzhou
scheme or table, p. 919 - 926 (2011/04/15)
We reported the synthesis, hypoxic cytotoxic activities and selectivities of 18 new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides. The synthesized compounds were screened in vitro against 5 cell lines: K562, SMMC-7721, A549, PC-3 and KB in hypoxia and in normoxia. Some of them showed higher or similar cytotoxic activity when compared to tirapazamine. Physico-chemical study showed the positive correlation between hypoxic activity and lipophilicity within a certain range. Preliminary mechanism study on the potent derivatives 4b, 4l and 4m indicated that the cytotoxic activities of these compounds might be mediated by inducing apoptosis.
