Reaction of trifluoroacetaldehyde with amino acids, nucleotides, lipid nucleophiles, and their analogs.
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.
Yin
H
H
Department of Pharmacology, University of Rochester, New York 14642, USA.
Crowder
R J
RJ
Jones
J P
JP
Anders
M W
MW
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000737:chemistry; D000111:Acetylcysteine / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D003543:Cysteamine / Q000737:chemistry; D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry; D003568:Cytidine Monophosphate / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry; D006157:Guanosine Monophosphate / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D013237:Stereoisomerism
D000596:Amino Acids; D018736:DNA Adducts; D008055:Lipids; D003543:Cysteamine; C055298:trifluoroacetaldehyde; D006157:Guanosine Monophosphate; D000255:Adenosine Triphosphate; D003568:Cytidine Monophosphate; D005978:Glutathione; D000079:Acetaldehyde; D003545:Cysteine; C017507:mecysteine; D000111:Acetylcysteine