- Putative electron-affinic radiosensitizers and markers of hypoxic tissue: Synthesis and preliminary in vitro biological characterization of C3-amino-substituted benzotriazine dioxides (BTDOs)
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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.
- Elsaidi, Hassan RH.,Yang, Xiao-Hong,Ahmadi, Fatemeh,Weinfeld, Michael,Wiebe, Leonard I.,Kumar, Piyush
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- 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)
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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.
- Johnson, Kevin M.,Parsons, Zachary D.,Barnes, Charles L.,Gates, Kent S.
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Read Online
- ORGANIC COMPOUND AND ORGANIC ELECTROLUMINESCENT DEVICE USING THE SAME
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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.
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Paragraph 0180-0183
(2021/07/06)
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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; 0077-0079
(2020/06/02)
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- 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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supporting information
p. 9978 - 9981
(2020/09/23)
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- 3-Substituted Benzo[ e][1,2,4]triazines: Synthesis and Electronic Effects of the C(3) Substituent
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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.
- Bodzioch, Agnieszka,Pomik?o, Dominika,Celeda, Ma?gorzata,Pietrzak, Anna,Kaszyński, Piotr
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p. 6377 - 6394
(2019/05/24)
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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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- 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
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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.
- 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.
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p. 155 - 160
(2017/02/05)
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- Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4- benzotriazine-1,4-dioxide derivatives
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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.
- Xia, Qing,Zhang, Ling,Zhang, Jun,Sheng, Rong,Yang, Bo,He, Qiaojun,Hu, Yongzhou
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scheme or table
p. 919 - 926
(2011/04/15)
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- Ureidobenzotriazine multiple H-bonding arrays: The importance of geometrical details on the stability of H-bonds
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(Chemical Equation Presented) A 3-ureidobenzo-1,2,4-triazine 1-N-oxide (1) was synthesized successfully. The derivative displays an acceptor-donor- acceptor-acceptor (ADAA) hydrogen-bonding motif in CDCl3 and DMSO-d6 solution as well as in the solid state. Although moderately strong association of 1 was observed with DAD motifs, nonspecific binding is observed with ureidopyridines featuring a complementary DADD array. Density functional calculations of conformations 1a and 1b together with two complexes revealed the clearly nonplanar geometry of the multiply hydrogen-bonded complex, in which some bonds are significantly longer (3.2 A) than is optimal for H-bonds. As a result, only very small free energies of association were calculated, in line with the experimentally observed absence of specific assembly of the components.
- Ligthart,Guo, Dawei,Spek,Kooijman, Huub,Zuilhof, Han,Sijbesma, Rint P.
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p. 111 - 117
(2008/09/17)
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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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- HETEROCYCLIC TRIAZINES AS HYPOXIC SELECTIVE PROTEIN KINASE INHIBITORS
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The invention relates to novel heterocyclic triazines which are useful as hypoxic selective cytotoxic agents that mediate and/or inhibit cell proliferation, for example, through the activity of protein kinases. The invention is further related to pharmaceutical compositions containing such compounds and compositions, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation by administering effective amounts of such compounds.
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Page/Page column 43; 56
(2010/11/25)
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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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- Time-resolved spectroscopy of the excited singlet states of tirapazamine and desoxytirapazamine
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Laser flash photolysis (LFP, 400 nm excitation) of the anti-cancer drug tirapazamine (TPZ) in acetonitrile produces the singlet excited-state S 1 with λmax = 544 nm. The lifetime of this state is 130 ps, in good agreement with the reported fluorescence lifetime. The excited state is reduced to the corresponding radical anion by KSCN or KI. The spectrum of the radical anion is in good agreement with previously reported pulse radiolysis studies and time-dependent density functional theory (TD-DFT) calculations. LFP of desoxytirapazamine (dTPZ) also produces the first excited singlet state, S1. The fluorescence quantum yield and lifetime (5.4 ns) of the dTPZ singlet excited state are both much greater than the corresponding values of TPZ. This is explained by DFT calculations that predict that cyclization of TPZ to form an oxaziridine is thermodynamically facile but that cyclization of dTPZ to form an oxadiaziridine is not. Thus, the S 1 state of TPZ has a short lifetime and low fluorescence quantum yield due to ready cyclization whereas the cyclization of the S1 state of dTPZ is unimportant and does not limit either the fluorescence quantum yield or the fluorescence lifetime. This conclusion is confirmed by studies of dTPZ', an isomer of dTPZ containing the C=N-O moiety which has a low quantum yield and short fluorescence lifetime similar to that of TPZ.
- Shi, Xiaofeng,Poole, James S.,Emenike, Ijeoma,Burdzinski, Gotard,Platz, Matthew S.
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p. 1491 - 1496
(2007/10/03)
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- Benzoazine mono-N-oxides and benzoazine 1,4 dioxides and compositions therefrom for the therapeutic use in cancer treatments
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The present invention relates to a synergetistic composition comprising one or more benzoazine-mono-N-oxides, and one or more benzoazine 1,4 dioxides for use in cancer therapy. The invention also provides a range of novel 1,2,4 benzoazine-mono-N-oxides and related analogues. These can be used as potentiators of the cytotoxicity of existing anticancer drugs and therapies for cancer treatment.
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- Benzoazine mono-N-oxides and benzoazine 1,4 dioxides and compositions therefrom for the therapeutic use in cancer treatments
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The present invention relates to a synergetistic composition comprising one or more benzoazine-mono-N-oxides, and one or more benzoazine 1,4 dioxides for use in cancer therapy. The invention also provides a range of novel 1,2,4 benzoazine-mono-N-oxides and related analogues. These can be used as potentiators of the cytotoxicity of existing anticancer drugs and therapies for cancer treatment.
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Page/Page column 37; 74
(2010/02/08)
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- DNA-TARGETED BENZOTRIAZINE 1,4-DIOXIDES AND THEIR USE IN CANCER THERAPY
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The present invention relates to DNA-targeted 1,2,4-benzotriazine- 1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
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- New and versatile syntheses of 3-alkyl- and 3-aryl-1,2,4-benzotriazine 1,4-dioxides: Preparation of the bioreductive cytotoxins SR 4895 and SR 4941
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Palladium-mediated coupling of 3-chloro-1,2,4-benzotriazine 1-oxide with a variety of stannanes in the presence of Pd(PPh3)4 gives 3-alkyl derivatives in good yields. Suzuki reaction of the 3-chloro compound with phenylboronic acids gives 3-aryl-1,2,4-benzotriazine 1-oxides. Oxidation of 1-oxides with trifluoroperacetic acid gives the 1,4-dioxides. This method provides a better route to the potential anti-cancer agents SR 4895 and SR 4941.
- Hay, Michael P.,Denny, William A.
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p. 9569 - 9571
(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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- Benzotriazines, pharmaceutical compositions, and methods of using same
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Use of compounds of the formula I STR1 in which R1 signifies an amino, C1 -C6 -alkylamino, di-C1 -C6 -alkylamino or a hydroxyl group, R2 and R3, which are the same or different, each hydrogen, halogen, C1 -C6 -alkyl, C1 -C6 -alkoxy, cyano, carboxyl, halogen-C1 -C6 -alkyl, cyano-C1 -C6 -alkyl, carboxy-C1 -C6 -alkyl, C1 -C6 - alkyl, hydroxyl, carboxy-C1 -C6 -alkoxy, C1 -C6 -alkoxycarbonyl-C1 -C6 -alkoxy or aminocarbonyl-C1 -C6 -alkoxy, C1 -C6 -alkylaminocarbonyl-C1 -C6 -alkoxy or di-C1 -C6 -alkylaminocarbonyl-C1 -C6 -alkoxy and n the number 0 or 1, their tautomers, as well as salts with non-toxic acids or bases, for the preparation of medicaments with PLA2 -inhibiting action, new compounds and process for their preparation.
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- Direct evidence for bimodal DNA damage induced by tirapazamine
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The ability of tirapazamine (1, 3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233) to fix DNA radical lesions is demonstrated by studying the reaction between the antitumor drug and an oligonucleotide radical that is independently produced at a defined site within a biopolymer: Using β- mercaptoethanol as a competitor, it was determined that tirapazamine traps a C1'-nucleotide radical with a rate constant of ~2 x 108 M-1 s-1. Product and isotopic labeling studies suggest that tirapazamine reacts with the radical via covalent adduct formation, resulting primarily from reaction at the N-oxide oxygen. Intermediate covalent adducts could not be observed, but are postulated to decompose to the alkaline labile 2'-deoxyribonolactone lesion. These experiments affirm recent proposals suggesting that tirapazamine can serve as a surrogate for O2 in converting DNA radicals into toxic strand damage events.
- Scott Daniels,Gates, Kent S.,Tronche, Christopher,Greenberg, Marc M.
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p. 1254 - 1257
(2007/10/03)
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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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p. 855 - 857
(2007/10/03)
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