Einige neue Abkömmlinge des Dioxindols

Kohn, Moritz; Ostersetzer, Alfons

doi:10.1007/bf01826722

Cited by 17 publications

(7 citation statements)

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“…Synthesis. 3-Hydroxy-3-methyloxindole was prepared by adding CH3MgBr to indole-2,3-dione in anhydrous THF according to a published method (17). The product was recrystallized from ether/CH2Cl2 and produced white crystals with a melting point of 160-161 °C, in 65% purified yield.…”

Section: Methodsmentioning

confidence: 99%

Evidence Supporting the Formation of 2,3-Epoxy-3-methylindoline: A Reactive Intermediate of the Pneumotoxin 3-Methylindole

Skordos

Skiles

Laycock

et al. 1998

Chem. Res. Toxicol.

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The existence of a cytochrome P450-dependent 2,3-epoxide of the potent pneumotoxin 3-methylindole was indirectly confirmed using stable isotope techniques and mass spectrometry. Determination of hydride shift and incorporation of labeled oxygen in 3-methyloxindole and 3-hydroxy-3-methyloxindole, metabolites that may be in part dependent on the presence of the epoxide, were utilized as indicators of the epoxide's existence. One mechanism for the formation of 3-methyloxindole involves cytochrome P450-mediated epoxidation followed by ring opening requiring a hydride shift from C-2 to C-3. Through incubations of goat lung microsomes with [2-2H]-3-methylindole, the retention of 2H in 3-methyloxindole was found to be 81%, indicating a majority of the oxindole was produced by the mechanism described above. 3-Hydroxy-3-methylindolenine is an imine reactive intermediate that could be produced by ring opening of the 2,3-epoxide. The imine may be oxidized to 3-hydroxy-3-methyloxindole by the cytosolic enzyme aldehyde oxidase. Activities of this putative detoxification enzyme were determined in both hepatic and pulmonary tissues from goats, rats, mice, and rabbits, but the activities could not be correlated to the relative susceptibilities of the four species to 3-methylindole toxicity. The 18O incorporation into either 3-methyloxindole or 3-hydroxy-3-methyloxindole from both 18O2 and H218O was determined. The 18O incorporation into 3-methyloxindole from 18O2 was 91%, strongly implicating a mechanism requiring cytochrome P450-mediated oxygenation. Incorporation of 18O into 3-hydroxy-3-methyloxindole indicated that the alcohol oxygen originated from molecular oxygen, also implicating an epoxide precursor. These studies demonstrate the existence of two new reactive intermediates of 3-methylindole and describe the mechanisms of their formation and fate.

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Section: Methodsmentioning

confidence: 99%

Evidence Supporting the Formation of 2,3-Epoxy-3-methylindoline: A Reactive Intermediate of the Pneumotoxin 3-Methylindole

Skordos

Skiles

Laycock

et al. 1998

Chem. Res. Toxicol.

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“…Synthesis of 3-Hydroxy-3-methyloxindole. 3-Hydroxy-3methyloxindole was synthesized according the procedure of Kohn and Ostersetzer (36) by adding CH3MgBr to isatin in anhydrous THF. The product was recrystallized from ether/CH2C12 to produce a white crystalline solid with a mp of 160-161 °C [lit.…”

Section: Methodsmentioning

confidence: 99%

“…The product was recrystallized from ether/CH2C12 to produce a white crystalline solid with a mp of 160-161 °C [lit. (36) 160 °C] in 65% purified yield.…”

Section: Methodsmentioning

confidence: 99%

Isolation and identification of 3-hydroxy-3-methyloxindole, the major murine metabolite of 3-methylindole

Skiles¹,

Adams²,

Yost³

1989

Chem. Res. Toxicol.

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3-Methylindole (3MI) is pneumotoxic to ruminants and rodents subsequent to metabolic oxidative activation by cytochrome P-450 monooxygenases. Goats are much more susceptible than mice and rats to 3MI-mediated lung damage, and these differences in species susceptibility may be reflected by differences in the metabolic products of 3MI. Radioactive 3MI was administered ip to Swiss-Webster mice, and the major nonpolar urinary metabolites were fractionated and separated by HPLC. Although 3-methyloxindole has been shown to be the major urinary metabolite of 3MI in goats, it was not detected in mouse urine. Instead, the major metabolite, 3-hydroxy-3-methyloxindole, was isolated and purified and its structure elucidated by 1H and 13C NMR, mass spectrometry, and IR spectroscopy. This is the first identification of this highly oxidized indole from mammalian sources. The production of this metabolite may be indicative of the formation of an electrophilic methyleneoxindole intermediate, which could be responsible for pneumotoxicity in this species.

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“…The reactions of isatin and its derivatives with Grignard reagents have been studied by Kohn and coworkers (238,239,242,243,244), by Myers and Lindwall (310), and by other workers (205,369,370,373,381,387,389) Grignard reagents isatin yields the corresponding 3-alkyl (or aryl)-3-hydroxyoxindoles (I). Kohn (243) found that when phenylmagnesium bromide and IV-methylisatin were allowed to react in equimolecular proportions the analogous l-methyl-3-phenyl-3-hydroxyoxindole (II) was obtained.…”

Section: A Reaction With Grignard Reagentsmentioning

confidence: 99%