Chiral inversion and hydrolysis of thalidomide: Mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites

The chiral inversion and hydrolysis of thalidomide and the catalysis by bas es and human serum albumin were investigated by using a stereoselective HPL C assay. Chiral inversion was catalyzed by albumin, hydroxyl ions, phosphat e, and amino acids, Basic amino acids (Arg and Lys) had a superior potency in catalyzing chiral inversion compared to acid and neutral ones. The chira l inversion of thalidomide is thus subject to specific and general base cat alysis, and it is suggested that the ability of HSA to catalyze the reactio n is due to the basic groups of the amino acids Arg and Lys and not to a si ngle catalytic site on the macromolecule. The hydrolysis of thalidomide was also base-catalyzed. However, albumin had no effect on hydrolysis, and the re was no difference between the catalytic potencies of acidic, neutral, an d 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 gene ral base catalysis, whereas hydrolysis is thought to occur by nucleophilic substitution involving specific and general base as well as nucleophilic ca talysis. As nucleophilic attack is sensitive to steric properties of the ca talyst, steric hindrance might be the reason albumin is not able to catalyz e hydrolysis. H-1 NMR experiments revealed that the three teratogenic metab olites of thalidomide, in sharp contrast to the drug itself, had complete c hiral stability. This leads to the speculation that, were some enantioselec tivity to exist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stable teratogenic metabolites.