Chiral Inversion and Hydrolysis of Thalidomide:  Mechanisms and Catalysis by Bases and Serum Albumin, and Chiral Stability of Teratogenic Metabolites

Abstract

The 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.

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

“…Hence, few reports disclose rate constants for racemization under aqueous conditions 1, 15, 16, 17, 18, 19, 20. Chiral centers with certain combinations of substituents have been posited to be prone to general‐base‐catalyzed racemization although with little supporting data 21, 22, 23…”

Supramolecular dynamics of thalidomide and its derivatives in water‐sediment system

“…The values of rate constants of the chiral interconversions for thalidomide and its derivatives are given in Table 6, which indicates higher rate of chiral interconversions of S-enantiomers of thalidomide and its derivatives. The values of rate constants were 0.390 and 0.385 day 21 for S-and R-enantiomers respectively, indicating slightly higher tendency of racemization of S-thalidomide. The effects of pH and temperature were studied on the chiral interconversions of thalidomide enantiomers.…”

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

“…[1] Thes tatus quo in enantioselective synthesis thus ignores the cruel blind spot that we address in this paper:racemization.…”

“…[13,14] Hence,f ew reports disclose rate constants for racemization under aqueous conditions. [1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data. [21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database.…”

“…The35compounds studied fall into fourteen chiral carbon atom types (A-N,T able 1) that have one hydrogen attached. [1,[15][16][17][18][19]31] Thes econd-order rate constants for generalbase-catalyzed racemization are plotted against SDDG at the bottom of Figure 2. When ac hiral center type is represented by more than one compound, the mean value of log(k gb )f or all representatives was used and the full range of values is shown as av ertical line.T his prevents any center type from dominating the linear fit.…”