Production of a reactive metabolite of troglitazone by electrochemical oxidation performed in nonaqueous medium

Tahara, Kayoko; Nishikawa, Takashi; Hattori, Yutaka; Iijima, Shiro; Kouno, Yukiko; Abe, Yoshihiro

doi:10.1016/j.jpba.2009.06.002

Cited by 16 publications

(6 citation statements)

References 17 publications

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“…Trapping experiments were performed with GSH and NAC, and the generated adducts were also found in HLM and RLM experiments [44]. These results were confirmed by Tahara and co-workers, who observed a reaction of the same reactive metabolite with a cysteine derivative [45].…”

Section: Adduct Formation Between Reactive Intermediates and Biomolecsupporting

confidence: 65%

“…After a defined reaction time, the reaction mixture can be directly analyzed by MS in case of the addition of amino acids, small peptides or other small nucleophiles, as shown in Fig. 2 acetaminophen quinone imine R = GSH, NAC, Cys, LGA [26][27][28][29][30] dopamine quinone R = GSH, NAC, PhSH [31][32][33] N-acetyldopamine quinone R = NAHis [34] diclofenac quinone imine quinone R = GSH, LGA [35,36] haloperidol iminium ion [37] niclosamide nitroso R = GSH [38] 3-trifluoromethyl-4-nitrophenol nitroso R = GSH [38] nilutamide nitroso R = GSH [38] clozapine nitrenium ion R = GSH, LGA, HSA [29,30,39] melarsoprol melarsen oxide R = GSH, HSA, Hb [40] (continued on next page) torimefene quinone methide R = GSH No structure determined, but: during reaction chlorine moiety is replaced by peptide [41] 3-tert-butyl-4-hydroxyanisole tert-butylhydroquinone quinone R = GSH [29] 3-methylindole quinone methide R = GSH [29] p-cresole 4-methylcatechol quinone R = GSH [29] 3,5-bis-tert-(butyl)-4-hydroxytoluene quinone methide R = GSH [29] trimethoprim imine methide R = GSH [29] amodiaquine quinone imines R = GSH, Cys, NAC, LGA [29,30,42,43] troglitazone quinone methide R = GSH, Cys, NAC [44,45] acebutolol quinone imines R = GSH [46] boscalid quinone imine R = GSH [47] (continued on next page) p-phenylenediamine quinone diimines R = GSH, Cys, LGA, HSA, Hb [48,49] eugenol quinone quinone methide R = GSH, LGA [50]...…”

Section: Adduct Formation Between Reactive Intermediates and Biomolecmentioning

confidence: 99%

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Adduct formation of electrochemically generated reactive intermediates with biomolecules

Büter

Vogel

Kärst

2015

TrAC Trends in Analytical Chemistry

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Section: Adduct Formation Between Reactive Intermediates and Biomolecsupporting

confidence: 65%

Section: Adduct Formation Between Reactive Intermediates and Biomolecmentioning

confidence: 99%

Adduct formation of electrochemically generated reactive intermediates with biomolecules

Büter

Vogel

Kärst

2015

TrAC Trends in Analytical Chemistry

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“…Several techniques can be used to find the optimal conditions. Those include cyclic voltammetry, direct EC-MS coupling, and off-line EC and LC-MS experiments [5, 22]. The latter method was applied in this study.…”

Section: Methodsmentioning

confidence: 99%

On-line electrochemistry–bioaffinity screening with parallel HR-LC-MS for the generation and characterization of modified p38α kinase inhibitors

Falck¹,

Vlieger²,

Giera³

et al. 2012

Anal Bioanal Chem

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In this study, an integrated approach is developed for the formation, identification and biological characterization of electrochemical conversion products of p38α mitogen-activated protein kinase inhibitors. This work demonstrates the hyphenation of an electrochemical reaction cell with a continuous-flow bioaffinity assay and parallel LC-HR-MS. Competition of the formed products with a tracer (SKF-86002) that shows fluorescence enhancement in the orthosteric binding site of the p38α kinase is the readout for bioaffinity. Parallel HR-MSn experiments provided information on the identity of binders and non-binders. Finally, the data produced with this on-line system were compared to electrochemical conversion products generated off-line. The electrochemical conversion of 1-{6-chloro-5-[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl]-3aH-indol-3-yl}-2-morpholinoethane-1,2-dione resulted in eight products, three of which showed bioaffinity in the continuous-flow p38α bioaffinity assay used. Electrochemical conversion of BIRB796 resulted, amongst others, in the formation of the reactive quinoneimine structure and its corresponding hydroquinone. Both products were detected in the p38α bioaffinity assay, which indicates binding to the p38α kinase.Electronic supplementary materialThe online version of this article (doi:10.1007/s00216-011-5663-2) contains supplementary material, which is available to authorized users.

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“…In the US, black box labels are warning about these side effects of the approved drugs rosiglitazone ( 8 ) and pioglitazone ( 9 ). Troglitazone ( 11 ) was withdrawn from the market because of its hepatotoxicity, which is, however, unrelated to PPARγ, but rather associated with the incorporation of a tocopherol-like component into the molecule ( Figure 2 ) leading to a reactive metabolite [ 232 , 233 ]. Despite these limits, the consideration of neuroprotective and especially mitochondrial effects by thiazolidinediones should be of value for mechanistic reasons and may be recalled if other PPARγ activators having a different pharmacological profile will be developed in the future.…”

Section: Thiazolidinedionesmentioning

confidence: 99%

Neuroprotection by Radical Avoidance: Search for Suitable Agents

Hardeland

2009

Molecules

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Neurodegeneration is frequently associated with damage by free radicals. However, increases in reactive oxygen and nitrogen species, which may ultimately lead to neuronal cell death, do not necessarily reflect its primary cause, but can be a consequence of otherwise induced cellular dysfunction. Detrimental processes which promote free radical formation are initiated, e.g., by disturbances in calcium homeostasis, mitochondrial malfunction, and an age-related decline in the circadian oscillator system. Free radicals generated at high rates under pathophysiological conditions are insufficiently detoxified by scavengers. Interventions at the primary causes of dysfunction, which avoid secondary rises in radical formation, may be more efficient. The aim of such approaches should be to prevent calcium overload, to reduce mitochondrial electron dissipation, to support electron transport capacity, and to avoid circadian perturbations. L-Theanine and several amphiphilic nitrones are capable of counteracting excitotoxicity and/or mitochondrial radical formation. Resveratrol seems to promote mitochondrial biogenesis. Mitochondrial effects of leptin include attenuation of electron leakage. Melatonin combines all the requirements mentioned, additionally regulates anti- and pro-oxidant enzymes and is, with few exceptions, very well tolerated. In this review, the perspectives, problems and limits of drugs are compared which may be suitable for reducing the formation of free radicals.

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Production of a reactive metabolite of troglitazone by electrochemical oxidation performed in nonaqueous medium

Cited by 16 publications

References 17 publications

Adduct formation of electrochemically generated reactive intermediates with biomolecules

Adduct formation of electrochemically generated reactive intermediates with biomolecules

On-line electrochemistry–bioaffinity screening with parallel HR-LC-MS for the generation and characterization of modified p38α kinase inhibitors

Neuroprotection by Radical Avoidance: Search for Suitable Agents

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