Nitrones and nitronic acid derivatives: Their structure and their roles in synthesis

Breuer, Eli

doi:10.1002/9780470772195.ch2

Cited by 20 publications

(13 citation statements)

References 338 publications

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“…This metabolite (M4) was identified and characterized in this study. A typical reaction of nitrone is the cycloaddition to other 1,3-diploes (either homo-or hetero-) (Hamer and Macaluso, 1964;Breuer, 1989). It has been known that a six-membered cyclic nitrone, 3,4,5,6-tetrahydropyridine N-oxide, could be dimerized by this cycloaddition mechanism as a result of dipole-dipole interaction (Hamer and Macaluso, 1964;Breuer, 1989).…”

Section: Discussionmentioning

confidence: 99%

Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel “Aromatase” Process

Sun¹,

Ehlhardt²,

Kulanthaivel³

et al. 2007

J Pharmacol Exp Ther

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Indoline derivatives possess therapeutic potential within a variety of drug candidates. In this study, we found that indoline is aromatized by cytochrome P450 (P450) enzymes to produce indole through a novel dehydrogenation pathway. The indole products can potentially be bioactivated to toxic intermediates through an additional dehydrogenation step. For example, 3-substituted indoles like 3-methylindole and zafirlukast [4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide] are dehydrogenated to form 3-methyleneindolenine electrophiles, which react with protein and/or DNA nucleophilic residues to cause toxicities. Another potentially significant therapeutic consequence of indoline aromatization is that the product indoles might have dramatically different therapeutic potency than the parent indolines. In this study, indoline was indeed efficiently aromatized by human liver microsomes and by several P450s, but not by flavin-containing monooxygenase (FMO) 3. CYP3A4 had the highest aromatase activity. Four additional indoline metabolites [2,3,4,7-tetrahydro-4,5-epoxy-1H-indole (M1); N-hydroxyindole (M2), N-hydroxyindoline (M3), and M4 ([1,4,2,5]dioxadiazino[2,3-a:5,6-aЈ]diindole)] were characterized; none was a metabolite of indole. M1 was an arene oxide from P450 oxidation, and M2, M3, and M4 were produced by FMO3. Our data indicated that indoline was oxidized to M3 and then to an intermediate indoline nitrone, which tautomerized to form M2, and subsequently dimerized to a di-indoline. This dimer was immediately oxidized by FMO3 or atmospheric oxygen to the final product, M4. No evidence was found for the P450-mediated production of an aliphatic alcohol from indoline that might dehydrate to produce indole. Therefore, P450 enzymes catalyze the novel "aromatase" metabolism of indoline to produce indole. The aromatase mechanism does not seem to occur through N-oxidation or dehydration of an alcohol but rather through a formal dehydrogenation pathway.Indoline, 2,3-dihydroindole, is a "saturated" structural analog of indole. Indoline-containing drugs have been utilized as drug candidates in a variety of therapeutic fields and are more frequently employed in new therapeutic entities in recent years. Indolines have been widely investigated as serotonin receptor agonists or antagonists. Examples include: SB-242084, a selective 5-HT 2C receptor antagonist with anxiolytic activity (Bromidge et al., 1997); SB-224289, a selective 5-HT 1B receptor antagonist with negative intrinsic activity (Selkirk et al., 1998); and 1-(1-indolinyl)-2-propylamine, a 5-HT 2C receptor agonist for the treatment of obesity (Bentley et al., 2004). A series of potent factor Xa inhibitors, the indoline derivatives of DX-9065a, could be novel antithrombotics for the treatment and prevention of thromboembolic diseases . Another indoline derivative, 5-amino-1-(3,5-dimethylphenyl)-indoline, was reported as a selective cyclooxygenase-1 inhibitor for its antiangiogenic property (Sano et al., 2006). Other...

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Section: Discussionmentioning

confidence: 99%

Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel “Aromatase” Process

Sun¹,

Ehlhardt²,

Kulanthaivel³

et al. 2007

J Pharmacol Exp Ther

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“…The resonance at d 154-155 ppm originates from sodium nitronate or oximes (E, Z). A plausible explanation for the formation of oximes is the reaction of 2-nitropropene with the oxygen nucleophile of the nitro/nitronic acid functionality and subsequent decomposition to an oxime and 2-nitro-1-propanal (Breuer, 1982).…”

Section: Analysis Of 2-nitroalkyl Polysaccharide Ethersmentioning

confidence: 99%

“…Side products, such as allyl groups (resulting from the elimination of nitrite (Breuer, 1982), allyl pullulan d 120 ppm) and 2-oxopropyl groups (Nef reaction, d 204-205 (March, 1985)) are incorporated into the polysaccharide to some extent (see Scheme 4 [Products obtained in the synthesis of 2-nitropropylpullulan (the bold values are chemical shifts calculated (ADS program) for the corresponding methoxy compound (Pull Me), the uncertainty range is given between brackets)]). The resonance at d 154-155 ppm originates from sodium nitronate or oximes (E, Z).…”

Section: Analysis Of 2-nitroalkyl Polysaccharide Ethersmentioning

confidence: 99%

Synthesis and reduction of 2-nitroalkyl polysaccharide ethers

Heeres

Spoelma

Doren

et al. 2000

Carbohydrate Polymers

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Several 2-nitroalkyl polysaccharide ethers (from pullulan (1), guar (2), agarose (3), inulin (4), cellulose (5), Na-a-polyglucuronate (6) and hydroxyethyl cellulose (7)) were synthesized by reaction with 2-nitro-1-alkenes (2-nitro-1-propene and 2-nitro-1-butene) formed in situ from 2-nitroalkyl acetates. Moderate to high efficiencies are obtained in concentrated aqueous solution/suspension for addition to 1-4 and 7. Analysis of this new class of polysaccharide derivatives with the aid of labeled 2-nitropropyl-2-13 C pullulan revealed that the nitrogroup is a mixture of the nitroalkane and nitronic acid tautomers. Grafting of nitroalkenes is observed and, to a lesser extent, additional reactions of the nitro group (formation of carbonyl, oxime and allyl groups) take place.Reduction of 2-nitroalkyl polysaccharide ethers with Na 2 S 2 O 4 or Na 2 S 2 O 4 /NaBH 4 leads to complex polysaccharide ethers. The products obtained are most likely mixtures of starting material, nitroso compounds, hydroxylamines, hydroxypropyl ethers and sulfamates. ᭧

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“…C-(4-chlorophenyl)-N-phenylnitrone (N1) was synthesized and purified according to the existing procedure [18,19]. Benzalacetophenone (K1), anisalacetophenone (K2) and benzylidene-2-acetylpyridine (K3) were synthesized according to literature [31].…”

Section: Methodsmentioning

confidence: 99%

“…Nitrones, an important category of 1,3-dipolar species [13][14][15][16][17], undergo facile concerted [ π 4 s + π 2 s ]-cycloaddition to different dipolarophiles producing isoxazolidines which serve as a key step in a number of natural product syntheses [13,[18][19][20]. Nitrones are a family of such heterocyclic compounds that have been studied extensively [13][14][15][16][17][18][19][20][21][22] due to their stability.…”

Section: Introductionmentioning

confidence: 99%

Solvatochromism and Molecular Selectivity of C-(4-chlorophenyl)-N-phenylnitrone: A Photophysical Study

Salampuria¹,

Chaudhuri²,

Banerjee³

2012

OPJ

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The ground state interaction of C-(4-chlorophenyl)-N-phenylnitrone (N1) with three different ,-unsaturated ketones (K1 -K3) in very dilute solution (10) has been noticed through charge transfer band formation in the visible region. The experimentally measured transition dipole, ground state resonance energy and formation constants of the complexes indicate interaction selectivity of the acyclic nitrone (N1) for the ketones. Molar absorptivity of the absorbing complexes were determined for all the three N1/K (1:1) interacting systems in toluene. Experimental findings were well rationalized with the help of electron density based global electrophilicity and nucleophilicity indices as well as with frontier molecular orbital calculations.

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Nitrones and nitronic acid derivatives: Their structure and their roles in synthesis

Cited by 20 publications

References 338 publications

Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel “Aromatase” Process

Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel “Aromatase” Process

Synthesis and reduction of 2-nitroalkyl polysaccharide ethers

Solvatochromism and Molecular Selectivity of C-(4-chlorophenyl)-N-phenylnitrone: A Photophysical Study

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