REACTION OF TRIFLUOROACETALDEHYDE WITH AMINO-ACIDS, NUCLEOTIDES, LIPID NUCLEOPHILES, AND THEIR ANALOGS

Trihaloacetaldehydes are used as sedatives, are key intermediates in t he metabolism of 1,1,1,2-tetrahaloethanes, some of which are chloroflu orocarbon substitutes, and are metabolites of trihaloethanols, which a re intestinal and bone marrow toxins. In the present study, trifluoroa cetaldehyde was used as a model to examine the reactions of trihaloace taldehydes with cellular nucleophiles, including amino acids, nucleoti des, 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 identifi ed as (2R,4R)- and S,4R)-2-(trifluoromethyl)thiazolidine-4-carboxylic acid. The absolute stereochemistry of (2R,4R)- and (2S,4R)-2-(trifluor omethyl)thiazolidine-4 acid was determined by homonuclear Overhauser e ffect experiments. The diastereoisomers were formed in a 2.8:1 ratio a t 37 degrees C and in a 1:4.0 ratio at 80 degrees C. Trifluoroacetalde hyde also reacted with L-cysteine methyl ester and 2-mercaptoethylamin e to form stable thiazolidine derivatives, but did not react with N-ac etyl-L-cysteine. The reaction of trifluoroacetaldehyde with the amino groups of ATP, GMP, CMP, L-citrulline, and urea resulted in the format ion of stable imines. TMP, which lacks an exocyclic amino group, did n ot react. Glutathione reacted with trifluoroacetaldehyde to form (2R,5 R)- and xymethyl)imino]-2-(trifluoromethyl)-1,3-oxathiane, whose forma tion was accompanied by simultaneous cleavage of the glutamyl moiety. The reactivity of nucleophilic groups with trifluoroacetaldehyde follo ws 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 invest igation. The reaction of trifluoroacetaldehyde with L-cysteine and glu tathione may afford routes for the stereoselective synthesis of cystei ne prodrugs and five- or six-membered heterocyclic compounds.