Chiral Inversion and Hydrolysis of Thalidomide: Mechanisms and Catalysis by Bases and Serum Albumin, and Chiral Stability of Teratogenic Metabolites
详细信息 查看全文
- 作者：Marianne Reist ; Pierre-Alain Carrupt ; Eric Francotte ; and Bernard Testa
- 刊名：Chemical Research in Toxicology
- 出版年：1998
- 出版时间：December 1998
- 年：1998
- 卷：11
- 期：12
- 页码：1521 - 1528
- 全文大小：244K
- 年卷期：v.11,no.12(December 1998)
- ISSN：1520-5010
文摘
The chiral inversion and hydrolysis of thalidomide and the catalysis by bases and humanserum albumin were investigated by using a stereoselective HPLC assay. Chiral inversionwas catalyzed by albumin, hydroxyl ions, phosphate, and amino acids. Basic amino acids (Argand Lys) had a superior potency in catalyzing chiral inversion compared to acid and neutralones. 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 groupsof the amino acids Arg and Lys and not to a single catalytic site on the macromolecule. Thehydrolysis of thalidomide was also base-catalyzed. However, albumin had no effect onhydrolysis, and there was no difference between the catalytic potencies of acidic, neutral, andbasic amino acids. This may be explained by different reaction mechanisms of the chiralinversion and hydrolysis of thalidomide. Chiral inversion is deduced to occur by electrophilicsubstitution involving specific and general base catalysis, whereas hydrolysis is thought tooccur by nucleophilic substitution involving specific and general base as well as nucleophiliccatalysis. As nucleophilic attack is sensitive to steric properties of the catalyst, steric hindrancemight be the reason albumin is not able to catalyze hydrolysis. 1H NMR experiments revealedthat the three teratogenic metabolites of thalidomide, in sharp contrast to the drug itself, hadcomplete chiral stability. This leads to the speculation that, were some enantioselectivity toexist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stableteratogenic metabolites.