Synthesis, single crystal X-ray structure and W-band (95 GHz) EPR spectroscopy of a new anionic isoindoline aminoxyl: synthesis and characterisation of some derivatives

Bottle, Steven E.; Gillies, Donald C.; Hughes, David L.; Micallef, Aaron S.; Smirnov, Alex I.; Sutcliffe, L. H.

doi:10.1039/b002497j

Cited by 34 publications

(38 citation statements)

References 24 publications

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“…Relative to 2 H 12 - 15 N-TMIO, the spectrum of 2 H 12 - 15 N-CTMIO shows a greater discrepancy in the signal intensity between the high and low field lines, suggesting that its motion in solution is more anisotropic in character. This has been previously observed for unlabelled CTMIO and attributed to the formation of hydrogen bonding dimers in solution [36, 39]. …”

Section: Resultssupporting

confidence: 72%

“…The isotopically labeled isoindoline nitroxides were synthesized according to established procedures [39-41], using appropriately labeled reactants and/or reagents. The EPR nitrogen manifolds of the deuterated compounds are free of the superhyperfine features that are readily observed in the spectrum of TMIO at 0% O 2 (but unresolved at high O 2 concentrations).…”

Section: Resultsmentioning

confidence: 99%

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The evaluation of new and isotopically labeled isoindoline nitroxides and an azaphenalene nitroxide for EPR oximetry

Khan

Blinco

Bottle

et al. 2011

Journal of Magnetic Resonance

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Isoindoline nitroxides are potentially useful probes for viable biological systems, exhibiting low cytotoxicity, moderate rates of biological reduction and favorable Electron Paramagnetic Resonance (EPR) characteristics. We have evaluated the anionic (5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl; CTMIO), cationic (5-(N,N,N-trimethylammonio)-1,1,3,3-tetramethylisoindolin-2-yloxyl iodide, QATMIO) and neutral (1,1,3,3-tetramethylisoindolin-2-yloxyl; TMIO) nitroxides and their isotopically labeled analogues (2H12- and/or 2H12-15N-labeled) as potential EPR oximetry probes. An active ester analogue of CTMIO, designed to localize intracellularly, and the azaphenalene nitroxide 1,1,3,3-tetramethyl-2,3-dihydro-2-azaphenalen-2-yloxyl (TMAO) were also studied. While the EPR spectra of the unlabeled nitroxides exhibit high sensitivity to O2 concentration, deuteration resulted in a loss of superhyperfine features and a subsequent reduction in O2 sensitivity. Labeling the nitroxides with 15N increased the signal intensity and this may be useful in decreasing the detection limits for in vivo measurements. The active ester nitroxide showed approximately 6% intracellular localization and low cytotoxicity. The EPR spectra of TMAO nitroxide indicated an increased rigidity in the nitroxide ring, due to dibenzo-annulation.

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Section: Resultssupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

The evaluation of new and isotopically labeled isoindoline nitroxides and an azaphenalene nitroxide for EPR oximetry

Khan

Blinco

Bottle

et al. 2011

Journal of Magnetic Resonance

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“…Both tetraethylation of 2-benzyl-5,6-dibromophthalimide (15) and cyanide coupling of 2-acetoxy-5,6-dibromo-1,1,3,3-tetraethylisoindoline (21) were unsuccessful. Similarly, oxidation of 2-benzyl-5,6-dimethyl-1,1,3,3-tetraethylisoindoline (24) and subsequent hydrolysis of the resulting benzamide 25 with acid or base failed to give the desired amine 26. The desired compound 4 could be obtained by conversion of 24 to the nitroxide, acetate protection of the nitroxide, oxidation of the methyl groups attached to the aromatic ring with permanganate and basic removal of the acetate group in an overall yield of 26 % yield (from 24).…”

Section: Discussionmentioning

confidence: 94%

“…[24] Treatment of 2-benzyl-1,1,3,3-tetraethylisoindoline (7) with bromine in the presence of anhydrous aluminium trichloride gave 2,5-dibromo-1,1,3,3-tetraethylisoindoline (8) in modest yield (30 %) (Scheme 1) after purification by column chromatography to remove the benzaldehyde which results from oxidative cleavage of the benzyl group by bromine. [25] Subsequent reduction of bromoamine 8 with hydrogen peroxide in the presence of sodium hydrogen carbonate afforded 5-bromo-1,1,3,3-tetraethylisoindoline (9) in high yield (98 %).…”

Section: Resultsmentioning

confidence: 99%

The Synthesis of Novel Isoindoline Nitroxides Bearing Water‐Solubilising Functionality

2009

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A range of novel tetramethyl‐ and tetraethylisoindolinenitroxides, possessing aryl‐linked carboxylic acids, amines, alcohols and phosphonic acids were prepared. Notably, the chemistry established for the aromatic dibromination of the tetramethylisoindolines was not easily transferred to the corresponding tetraethylisoindoline system. Instead, various tetraethylisoindoline analogues were accessed by the oxidation of methyl groups attached to the aromatic ring to give the carboxylic acids. The increased steric bulk of the tetraethyl structures should limit bio‐reduction and these compounds may have potential as antioxidants.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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“…[13,14] Starting from 2 months of age, groups of mice were given solubilized CTMIO in their drinking water, and this treatment was continued until mice were culled. This drug was given at 4µM or 40µM concentrations, which were previously reported to be well tolerated by mice.…”

Section: Tumor Induction and Nitroxide Dosingmentioning

confidence: 99%

Assessment of Tumor Prevention in Type 1 Neurofibromatosis using a Nitroxide Compound

El-Hoss

Micallef

Fairfull‐Smith

et al. 2011

Free Radicals and Antioxidants

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Background: Type 1 Neurofibromatosis (NF1) is a genetic disorder linked to mutations of the NF1 gene. Clinical symptoms are varied, but hallmark features of the disease include skin pigmentation anomalies (café au lait macules, skinfold freckling) and dermal neurofibromas. Method: These dermal manifestations of NF1 have previously been reported in a mouse model where Nf1 +/-mice are topically treated with dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). We adopted this mouse model to test the protective effects of a nitroxide antioxidant, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO). Antioxidants have previously been shown to increase longevity in nf1-deficient fruitflies. Doses of 4µM and 40µM CTMIO provided ad libitum in drinking water were given to Nf1-deficient mice. Results: Consistent with previous reports, Nf1-deficient mice showed a 4.7-fold increase in papilloma formation (P < 0.036). However, neither dose of CTMIO had any significant affect on papilloma formation. A non-significant decrease in skin pigmentation abnormalities was seen with 4µM but not 40µM CTMIO. Subsequent analysis of genomic DNA isolated from papillomas indicated that DMBA/TPA induced tumors did not exhibit a local loss of heterozygosity (LOH) at the Nf1 locus. Conclusion: These data reveal that oral antioxidant therapy with CTMIO does not reduce tumor formation in a multistage cancer model, but also that this model does not feature LOH for Nf1. IntroductIonType 1 Neurofibromatosis (NF1) is an autosomal dominant genetic disorder that affects 1:3,000-1:3,500 individuals and can lead to disorders in a range of tissues.[1] NF1 has tumor-suppressor function and encodes for neurofibromin, a negative regulator of oncogenic protein Ras.[2] A number of specific tumor types are associated with NF1, including cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, astrocytomas, and optic gliomas. While the cutaneous neurofibromas are often benign, their appearance is common during puberty and they can be cosmetically disfiguring and can have a dramatic impact on patient quality of life. Currently there are no preventative measures able to suppress the onset of dermal neurofibromas in NF1 patients. The causes of neurofibroma formation are linked to a clonal second hit on the NF1 gene. Assessment of tumor Prevention in type 1 neurofibromatosis using a nitroxide compound[3] For plexiform neurofibromas, a Krox20-cre; Nf1 flox/flox mouse model showed that double inactivation of NF1 in Schwann cells was critical for tumorigenesis.[4] However, this research also showed that interactions with Nf1 +/-mast cells were also important for potentiating tumor growth. A proportion of neurofibromas can progress to a more life-threatening outcome, a malignant peripheral nerve sheath tumor (MPNST). Coordinate loss of the master tumor suppressor P53 may be associated with progression to an MPNST. [5,6] The coincidence of tumor formation with puberty has historically led to speculation of an activation ...

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Synthesis, single crystal X-ray structure and W-band (95 GHz) EPR spectroscopy of a new anionic isoindoline aminoxyl: synthesis and characterisation of some derivatives

Cited by 34 publications

References 24 publications

The evaluation of new and isotopically labeled isoindoline nitroxides and an azaphenalene nitroxide for EPR oximetry

The evaluation of new and isotopically labeled isoindoline nitroxides and an azaphenalene nitroxide for EPR oximetry

The Synthesis of Novel Isoindoline Nitroxides Bearing Water‐Solubilising Functionality

Assessment of Tumor Prevention in Type 1 Neurofibromatosis using a Nitroxide Compound

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