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Chiral Inversion and Hydrolysis of Thalidomide: Mechanisms and Catalysis by Bases and Serum Albumin, and Chiral Stability of Teratogenic Metabolites
journal contribution
posted on 1998-11-06, 00:00 authored by Marianne Reist, Pierre-Alain Carrupt, Eric Francotte, Bernard TestaThe chiral inversion and hydrolysis of thalidomide and the catalysis by bases and human
serum albumin were investigated by using a stereoselective HPLC assay. Chiral inversion
was catalyzed by albumin, hydroxyl ions, phosphate, and amino acids. Basic amino acids (Arg
and Lys) had a superior potency in catalyzing chiral inversion compared to acid and neutral
ones. The chiral inversion of thalidomide is thus subject to specific and general base catalysis,
and it is suggested that the ability of HSA to catalyze the reaction is due to the basic groups
of the amino acids Arg and Lys and not to a single catalytic site on the macromolecule. The
hydrolysis of thalidomide was also base-catalyzed. However, albumin had no effect on
hydrolysis, and there was no difference between the catalytic potencies of acidic, neutral, and
basic amino acids. This may be explained by different reaction mechanisms of the chiral
inversion and hydrolysis of thalidomide. Chiral inversion is deduced to occur by electrophilic
substitution involving specific and general base catalysis, whereas hydrolysis is thought to
occur by nucleophilic substitution involving specific and general base as well as nucleophilic
catalysis. As nucleophilic attack is sensitive to steric properties of the catalyst, steric hindrance
might be the reason albumin is not able to catalyze hydrolysis. 1H NMR experiments revealed
that the three teratogenic metabolites of thalidomide, in sharp contrast to the drug itself, had
complete chiral stability. This leads to the speculation that, were some enantioselectivity to
exist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stable
teratogenic metabolites.