Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate

Chem Res Toxicol. 1996 Dec;9(8):1225-9. doi: 10.1021/tx9601566.


We propose that 3-carbamoyl-2-phenylpropionaldehyde is an intermediate in the metabolism of felbamate, an anti-epileptic drug with a unique profile of the 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 < or = 30 s) and to undergo facile elimination to 2-phenylpropenal, an alpha, beta-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 > or = 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 microM) comparable to the known unsaturated aldehyde toxins, 4-hydroxy-2-nonenal and acrolein. 3-Carbamoyl-2-phenylpropionaldehyde also exhibited significant cytotoxicity (GI50 = 53 +/- 8 microM), whereas 2-phenyl-1,3-propanediol monocarbamate (GI50 > 500 microM) and 3-carbamoyl-2-phenylpropionic acid (GI50 > 500 microM) 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldehydes / chemical synthesis
  • Aldehydes / chemistry*
  • Aldehydes / toxicity
  • Animals
  • Anticonvulsants / chemistry
  • Anticonvulsants / metabolism*
  • Anticonvulsants / toxicity
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cricetinae
  • Felbamate
  • Fibroblasts / drug effects
  • Guinea Pigs
  • Half-Life
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Phenylcarbamates
  • Propylene Glycols / chemistry
  • Propylene Glycols / metabolism*
  • Propylene Glycols / toxicity


  • 3-carbamoyl-2-phenylpropionaldehyde
  • Aldehydes
  • Anticonvulsants
  • Phenylcarbamates
  • Propylene Glycols
  • hydratropic aldehyde
  • Felbamate