Synthesis of substituted, 2,2,5,5‐tetramethylpyrrolidin‐l‐oxyl spin labels–<i>P</i>H sensitivity studies

Mathew, Abraham E.; Dodd, John R.

doi:10.1002/jhet.5570220153

Cited by 15 publications

(11 citation statements)

References 9 publications

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“…Subsequent elution with hexane/ether (1:1) afforded trans-3,4-dicyano-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (8a) (1.7 g; 46% yield), which was recrystallized from ether/hexane [mp ϭ 141-142°C; IR (CHCl 3 ): 2215 cm Ϫ1 (CN)]. Increasing the polarity of the solvent to hexane/ ether (1:2) eluted cis-3,4-dicyano-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (8b) (0.7 g; 18% yield), which was recrystallized from ether/ hexane [mp ϭ 84°C; IR (CHCl 3 ): 2220 cm Ϫ1 (CN)] (Mathew and Dodd, 1985).…”

Section: Methodsmentioning

confidence: 99%

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Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O₂ Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Miyake¹,

Shen²,

Liu³

et al. 2006

J Pharmacol Exp Ther

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Measurement of O 2 concentration and distribution in brain isessential to understanding the pathophysiology of stroke. Lowfrequency electron paramagnetic resonance (EPR) spectroscopy with a paramagnetic probe is an attractive imaging modality that can potentially map O 2 concentration in the brain. In a previous study, we demonstrated that, after intraperitoneal administration of 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (1) to mice, this nitroxide crossed the blood-brain barrier into brain tissue where, after hydrolysis, 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (2) was liberated and entrapped. This pilot study suggested that nitroxide 1 is a proimaging agent that can deliver nitroxide 2 to brain tissue, where O 2 levels can be estimated. In the present study, we conducted a series of pharmacokinetic and pharmacodynamic experiments designed to assess the uptake of structurally disparate nitroxides into brain tissue and retention, after hydrolysis, of the anions of the corresponding nitroxide acids. From these findings, nitroxide 1 and trans-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (5) meet the requirement as EPR proimaging agents for mapping O 2 distribution in the brain following stroke.

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Section: Methodsmentioning

confidence: 99%

“…The organic solution was dried over anhydrous MgSO 4 , filtered, and rotary evaporated to dryness, leaving a light yellow solid. Recrystallization from acetone/benzene afforded trans -3,4-dicarboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (6) (1 g; 89% yield; mp ϭ 222-224°C with decomposition) (Mathew and Dodd, 1985;Chatani et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O₂ Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Miyake¹,

Shen²,

Liu³

et al. 2006

J Pharmacol Exp Ther

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“…The 3,3-dicarboxy-2,2,5,5-tetra-methylpyrrolidine-1-oxyl (DCP) was prepared in analogy to original method [14,20] with some modifications described in [21]. The synthesis of nitroxides DCP-AM, DCP-AM2 [14] and DCAP-AM2 and of corresponding hydroxylamine DCP-AM-H is shown in Schemes 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

Cellular accumulation and antioxidant activity of acetoxymethoxycarbonyl pyrrolidine nitroxides

Dikalov

Dikalova

Morozov

et al. 2017

Free Radical Research

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Nitroxides are widely used in biology as antioxidants, spin labels, functional spin probes for pH, oxygen and thiol levels, and tissue redox status imaging using electron paramagnetic resonance (EPR); however, biological applications of nitroxides is hindered by fast bioreduction to EPR-silent hydroxylamines and rapid clearance. In this work, we have studied pyrrolidine nitroxides with acetoxymethoxycarbonyl groups which can undergo hydrolysis by cellular esterases to hydrophilic carboxylate derivatives resistant to bioreduction. Nitroxides containing acetoxymethoxycarbonyl groups were rapidly absorbed by cells from the media, 3,4-bis-(acetoxymethoxycarbonyl)-proxyl (DCP-AM2) and 3-(2-(bis(2-(acetoxymethoxy)-2-oxoethyl)amino)acetamido)-proxyl (DCAP-AM2) showing the strongest EPR signal of the cellular fraction. Remarkably, the EPR parameters of 3,4-dicarboxy-proxyl (DCP) and its mono- and di-acetoxymethyl esters are different, and consequent intracellular hydrolysis of acetoxymethoxycarbonyl groups in DCP-AM2 can be followed by EPR. To elucidate intracellular location of the resultant DCP, the mitochondrial fraction has been isolated. EPR measurements showed that mitochondria were the main place where DCP was finally accumulated. TEMPO derivatives showed expectedly much faster decay of EPR signal in the cellular fraction, compared to pyrrolidine nitroxides. It was found that supplementation of endothelial cells with 50 nM of DCP-AM2 completely normalised the mitochondrial superoxide level. Moreover, administration of DCP-AM2 to mice (1.4 mg/kg/day) resulted in substantial nitroxide accumulation in the tissues and significantly reduced hypertension. We found that hydroxylamine derivatives of dicarboxyproxyl nitroxide DCP-AM-H can be used for the detection of superoxide in vivo in angiotensin II model of hypertension. Infusion of DCP-AM-H in mice leads to accumulation of persistent EPR signal of nitroxide in the blood and vascular tissue in angiotensin II-infused wild-type but not in SOD2 overexpressing mice. Our data demonstrate that acetoxymethoxycarbonyl group containing nitroxides accumulate in mitochondria and demonstrate site-specific antioxidant activity.

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“…Cooling the solution at −10 °C yielded yellow crystals; mp = 141 – 142 °C. 35 IR (CHCl 3 ): 2229 (CN) cm −1 .…”

Section: Methodsmentioning

confidence: 99%

Designing Molecular Probes To Prolong Intracellular Retention: Application to Nitroxide Spin Probes

et al. 2016

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Targeted delivery of molecular probes into cells enables cellular imaging through optical and magnetic modalities. Probe molecules that are well retained by cells can accumulate to higher intracellular concentrations, and thus increase the signal-to-noise ratio of, and widen the temporal window for, imaging. Here we synthesize a paramagnetic spin probe bearing six ionic functional groups and show that it has long intracellular half-life (> 12 hours) and exceptional biostability in living cells. We demonstrate that judicious incorporation of ionic substituents on probe molecules systematically increases intracellular retention time, and should therefore be beneficial to imaging experiments.

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Synthesis of substituted, 2,2,5,5‐tetramethylpyrrolidin‐l‐oxyl spin labels–PH sensitivity studies

Cited by 15 publications

References 9 publications

Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O₂ Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O₂ Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Cellular accumulation and antioxidant activity of acetoxymethoxycarbonyl pyrrolidine nitroxides

Designing Molecular Probes To Prolong Intracellular Retention: Application to Nitroxide Spin Probes

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Synthesis of substituted, 2,2,5,5‐tetramethylpyrrolidin‐l‐oxyl spin labels–PH sensitivity studies

Cited by 15 publications

References 9 publications

Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O2 Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O2 Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Cellular accumulation and antioxidant activity of acetoxymethoxycarbonyl pyrrolidine nitroxides

Designing Molecular Probes To Prolong Intracellular Retention: Application to Nitroxide Spin Probes

Contact Info

Product

Resources

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Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O₂ Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O₂ Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study