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Synthesis and in Vitro Reactivity of 3-Carbamoyl-2-phenylpropionaldehyde and 2-Phenylpropenal:  Putative Reactive Metabolites of Felbamate

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Chemistry Department, University of Virginia, and Departments of Microbiology and Pathology, University of Virginia, Charlottesville, Virginia 22901
Cite this: Chem. Res. Toxicol. 1996, 9, 8, 1225–1229
Publication Date (Web):November 27, 1996
https://doi.org/10.1021/tx9601566
Copyright © 1996 American Chemical Society

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    Abstract

    We propose that 3-carbamoyl-2-phenylpropionaldehyde is an intermediate in the metabolism of felbamate, an anti-epileptic drug with a unique profile of therapeutic activity, and undergoes a cascade of chemical reactions responsible for the toxic properties of the parent drug. To test this hypothesis, we have synthesized 3-carbamoyl-2-phenylpropionaldehyde and evaluated its in vitro reactivity. This molecule was found to be highly unstable at physiological pH (t1/2 ≤ 30 s) and to undergo facile elimination to 2-phenylpropenal, an α,β-unsaturated aldehyde commonly termed atropaldehyde. However, the predominant reaction pathway for 3-carbamoyl-2-phenylpropionaldehyde was reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one, a urethane that has a considerably longer half-life at physiological pH (t1/2 ≥ 5 h) and may serve as a stable reservoir of the reactive aldehyde both in vitro and in vivo. Atropaldehyde is a potent electrophile and was found to exhibit cytotoxicity to cultured fibroblasts (50% growth inhibition (GI50) = 4.1 ± 1.1 μM) comparable to the known unsaturated aldehyde toxins, 4-hydroxy-2-nonenal and acrolein. 3-Carbamoyl-2-phenylpropionaldehyde also exhibited significant cytotoxicity (GI50 = 53 ± 8 μM), whereas 2-phenyl-1,3-propanediol monocarbamate (GI50 > 500 μM) and 3-carbamoyl-2-phenylpropionic acid (GI50 > 500 μM) were nontoxic. We have additionally demonstrated the formation of a glutathione−atropaldehyde conjugate from the in vitro incubation of 3-carbamoyl-2-phenylpropionaldehyde with glutathione. Thus, the potent cytotoxicity and potential allergenicity of atropaldehyde implicate this unsaturated aldehyde as a possible causative agent in the toxicities observed with felbamate treatment.

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     Chemistry Department, University of Virginia.

     Departments of Microbiology and Pathology, University of Virginia.

    *

     To whom correspondence should be addressed:  Timothy L. Macdonald, Chemistry Department, McCormick Rd., Charlottesville, VA 22901. E-mail:  [email protected].

     Abstract published in Advance ACS Abstracts, November 1, 1996.

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