Reverse reaction of thalidomide hydrolytic product to thalidomide for reconsidering metabolic pathway of thalidomide

2015 Fiscal Year Final Research Report

• Project/Area Number: 26620019
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Physical chemistry
• Research Institution: Waseda University
• Principal Investigator: Asahi Toru 早稲田大学, 理工学術院, 教授 (80222595)
• Co-Investigator(Kenkyū-buntansha): Masahito Tanaka 国立研究開発法人産業技術総合研究所, 研究員 (30386643)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: サリドマイド加水分解産物 / 脱水反応 / X線結晶構造解析 / HPLC分析 / 反応速度論 / 量子化学計算

Outline of Final Research Achievements

Recently, Thalidomide(TD) has attracted attention again because of rediscovery of drug efficacy against some intractable diseases. Previously, we found that α- (2-Carboxybenzamido) glutarimide (CBG), which is a primary hydrolysis product of TD in vivo, slowly changed to TD through dehydration in organic solvents such as acetonitrile. In this study, to comprehend its mechanisms, we investigated the dehydration of CBG under various conditions and examined whether the dehydration occur on phthaloylisoglutamine (PIG) and phthaloylglutamine (PG), which are other primary hydrolysis products of TD. We have concluded that the dehydration of CBG occurred in acetonitrile and ethanol within a range of 20-60 oC, whereas PIG and PG were not dehydrated in the condition described above. Moreover, the kinetics of CBG dehydration suggests that the reaction mechanism was not simple first-order reaction but catalytic reaction which involve both TD and CBG as a catalyst.

Free Research Field

キラル科学