Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate.
Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate.
复制标题
3-氨基甲酰基-2-苯基丙醛和2-苯基丙烯醛的合成和体外反应性：非氨酯的假定反应性代谢物。
DOI：
10.1021/tx9601566
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发表时间：
1996
影响因子：
4.1
通讯作者：
Macdonald,TL
中科院分区：
文献类型：
--
作者：
Thompson,CD;Kinter,MT;Macdonald,TL
我们认为3-氨基甲酰基-2-苯基丙醛是非氨酯代谢的中间体，非氨酯是一种具有独特治疗活性的抗癫痫药物，并经历了一系列化学反应，导致母体药物的毒性。为了验证这一假设，我们合成了3-氨基甲酰基-2-苯基丙醛，并评价了它的体外反应性。发现该分子在生理pH下高度不稳定（t1/2≤ 30 s），并容易消除为2-苯基丙烯醛（一种α，β-不饱和醛，通常称为阿托品醛）。然而，3-氨基甲酰基-2-苯基丙醛的主要反应途径是可逆环化以生成4-羟基-5-苯基四氢-1，3-恶嗪-2-酮，在生理pH下具有相当长的半衰期的氨基甲酸乙酯（t1/2≥ 5 h）在体外和体内都可以作为活性醛的稳定储存库。成纤维细胞（50%生长抑制（GI 50）= 4.1 ± 1.1 μM）与已知的不饱和醛毒素，4-羟基-2-壬烯醛和丙烯醛相当。3-氨基甲酰基-2-苯基丙醛也表现出显著的细胞毒性（GI 50 = 53 ± 8 μM），而2-苯基-1，3-丙二醇单氨基甲酸酯（GI 50> 500 μM）和3-氨基甲酰基-2-苯基丙酸（GI 50> 500 μM）则无毒性。我们还证明了3-氨基甲酰基-2-苯基丙醛与谷胱甘肽体外孵育形成谷胱甘肽-阿托品醛结合物。因此，阿托品醛的强效细胞毒性和潜在过敏性表明，这种不饱和醛可能是非氨酯治疗中观察到的毒性的致病因子。
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 itsin vitroreactivity. 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 bothin vitroandin 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 thein vitroincubation 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.