Application of Suzuki–Miyaura and Buchwald<i>–</i>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.

doi:10.1002/jhet.2559

Cited by 10 publications

(5 citation statements)

References 55 publications

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“…A collection of 25 1,2,4-benzotriazine 1-oxides was synthesized by published routes and minor modifications of published routes (Scheme ). ,,− The compounds in the collection contained various electron-donating and electron-withdrawing substituents. We performed preliminary measurements to determine whether any of the compounds displayed desirable photophysical properties such as high fluorescence quantum yields (Φ), large extinction coefficients (ε), and large brightness values (Φε) relative to the TPZ metabolite 4a .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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Hypoxia-selective cytotoxins (HSCs) seek to exploit the oxygenpoor 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 (3amino-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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…13 [1,2,4]triazine-1-oxide (5m). 72 Following the general procedure, N-oxide 5m (12.1 mg, 17% yield) was obtained as a pale yellow solid starting from N-(2-nitrophenyl)amidine 12m (53.1 mg, 0.259 mmol). Recrystallization from nheptane gave analytically pure product.…”

Section: -Phenylbenzo[e][124]triazine-1-oxide (5a)mentioning

confidence: 99%

3-Substituted Blatter Radicals: Cyclization of N-Arylguanidines and N-Arylamidines to Benzo[e][1,2,4]triazines and PhLi Addition

2023

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A series of 3-amino-and 3-alkyl-substituted 1-phenyl-1,4dihydrobenzo [e][1,2,4]triazin-4-yls was prepared in four steps involving Narylation, cyclization of N-arylguanidines and N-arylamidines, reduction of the resulting N-oxides to benzo[e][1,2,4]triazines, and subsequent addition of PhLi followed by aerial oxidation. The resulting seven C(3)-substituted benzo [e][1,2,4]triazin-4-yls were analyzed by spectroscopic and electrochemical methods augmented with density functional theory (DFT) methods. Electrochemical data were compared to DFT results and correlated with substituent parameters.

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“…The analogous C(3)-bromide is only mentioned in the literature, while the C(3)-iodide 1d is unknown. On the other hand, 3-chloro- ( 2c ), 3-bromo-, , and 3-iodo-benzo[ e ][1,2,4]triazine-1-oxides ( 2d ) have been successfully used in Pd-catalyzed C–C coupling reactions with a dozen substituted aromatic and heteroaromatic boronic acids (Suzuki conditions) , and several organotin reagents (Et 4 Sn, Me 4 Sn, Bu 3 SnCHCH 2 , and Bu 3 SnCH 2 CHCH 2 ; Stille conditions). − …”

Section: Introductionmentioning

confidence: 99%

3-Substituted Benzo[e][1,2,4]triazines: Synthesis and Electronic Effects of the C(3) Substituent

et al. 2019

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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 (C 5 H 11 ), (het)aryl (Ph, 2-thienyl, ferrocenyl), ArCC, amine (NHPh and morpholine), PO(OEt) 2 , sulfanyl (SBu-t), alkoxide (OEt, OMe), and CN. The synthesis of C(3)−CF 3 derivative 1g via the Ruppert reaction with 1d and its 1-oxide analogue 2d led to the substitution followed by formal addition of HCF 3 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 π−π*(1) transition energy and good correlation of the 1 H NMR chemical shift with the substituent constant σ p . 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.

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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

Cited by 10 publications

References 55 publications

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

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

3-Substituted Blatter Radicals: Cyclization of N-Arylguanidines and N-Arylamidines to Benzo[e][1,2,4]triazines and PhLi Addition

3-Substituted Benzo[e][1,2,4]triazines: Synthesis and Electronic Effects of the C(3) Substituent

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