Yin H, Crowder R J, Jones J P, Anders M W
Department of Pharmacology, University of Rochester, New York 14642, USA.
Chem Res Toxicol. 1996 Jan-Feb;9(1):140-6. doi: 10.1021/tx950072h.
Trihaloacetaldehydes are used as sedatives, are key intermediates in the metabolism of 1,1,1,2-tetrahaloethanes, some of which are chlorofluorocarbon substitutes, and are metabolites of trihaloethanols, which are intestinal and bone marrow toxins. In the present study, trifluoroacetaldehyde was used as a model to examine the reactions of trihaloacetaldehydes with cellular nucleophiles, including amino acids, nucleotides, and lipid components. Reaction of trifluoroacetaldehyde hydrate (10 mM) with amino acids (100 mM) in buffer at pH 7.0 and 30 degrees C showed that only L-cysteine formed stable adducts, which were identified as (2R,4R)- and (2S,4R)-2-(trifluoromethyl)thiazolidine-4-carboxylic acid. The absolute stereochemistry of (2R,4R)- and (2S,4R)-2-(trifluoromethyl)thiazolidine-4-carboxylic acid was determined by homonuclear Overhauser effect experiments. The diastereoisomers were formed in a 2.8:1 ratio at 37 degrees C and in a 1:4.0 ratio at 80 degrees C. Trifluoroacetaldehyde also reacted with L-cysteine methyl ester and 2-mercaptoethylamine to form stable thiazolidine derivatives, but did not react with N-acetyl-L-cysteine. The reaction of trifluoroacetaldehyde with the amino groups of ATP, GMP, CMP, L-citrulline, and urea resulted in the formation of stable imines. TMP, which lacks an exocyclic amino group, did not react. Glutathione reacted with trifluoroacetaldehyde to form (2R,5R)- and (2S,5R)-5-amino-6-[carboxymethyl)imino]-2-(trifluoromethyl)-1,3- oxathiane, whose formation was accompanied by simultaneous cleavage of the glutamyl moiety. The reactivity of nucleophilic groups with trifluoroacetaldehyde follows the order SH > NH2 > OH. The results of the present study indicate that trifluoroacetaldehyde covalently modifies cellular nucleophiles. The biological significance of these reactions warrants further investigation. The reaction of trifluoroacetaldehyde with L-cysteine and glutathione may afford routes for the stereoselective synthesis of cysteine prodrugs and five- or six-membered heterocyclic compounds.
三卤乙醛用作镇静剂，是1,1,1,2 - 四卤乙烷代谢过程中的关键中间体，其中一些是氯氟烃替代品，并且是三卤乙醇的代谢产物，三卤乙醇是肠道和骨髓毒素。在本研究中，三氟乙醛用作模型来研究三卤乙醛与细胞亲核试剂的反应，这些亲核试剂包括氨基酸、核苷酸和脂质成分。在pH 7.0和30℃的缓冲液中，三氟乙醛水合物（10 mM）与氨基酸（100 mM）反应表明，只有L - 半胱氨酸形成稳定的加合物，其被鉴定为（2R,4R） - 和（2S,4R） - 2 - （三氟甲基）噻唑烷 - 4 - 羧酸。通过同核Overhauser效应实验确定了（2R,4R） - 和（2S,4R） - 2 - （三氟甲基）噻唑烷 - 4 - 羧酸的绝对立体化学。在37℃时，非对映异构体以2.8:1的比例形成，在80℃时以1:4.0的比例形成。三氟乙醛还与L - 半胱氨酸甲酯和2 - 巯基乙胺反应形成稳定的噻唑烷衍生物，但不与N - 乙酰 - L - 半胱氨酸反应。三氟乙醛与ATP、GMP、CMP、L - 瓜氨酸和尿素的氨基反应导致形成稳定的亚胺。缺乏环外氨基的TMP不发生反应。谷胱甘肽与三氟乙醛反应形成（2R,5R） - 和（2S,5R） - 5 - 氨基 - 6 - [（羧甲基）亚氨基] - 2 - （三氟甲基） - 1,3 - 氧杂硫杂环戊烷，其形成伴随着谷氨酰部分的同时裂解。亲核基团与三氟乙醛的反应活性顺序为SH＞NH₂＞OH。本研究结果表明，三氟乙醛可共价修饰细胞亲核试剂。这些反应的生物学意义值得进一步研究。三氟乙醛与L - 半胱氨酸和谷胱甘肽的反应可能为半胱氨酸前药和五元或六元杂环化合物的立体选择性合成提供途径。
