Received for publication March 24, 2009.
Revised May 21, 2009.
Accepted for publication June 17, 2009.

Aromatic Substitution Reaction of 2-Chloropyridines Catalyzed by Microsomal Glutathione S-Transferase 1

Abstract

We investigated a substitution reaction of a series of 2-chloropyridine derivatives catalyzed by rat liver microsomal glutathione S-transferase 1 (MGST1). Various 2-chloropyridine derivatives were metabolized to the corresponding substituted glutathione conjugates via displacement of chlorine atom with glutathione. The reaction was affected by the electron-withdrawing strength and position of the substituents. Molecular orbital calculations on the change in Gibbs free energy between the initial and transition states verified the presence of a Meisenheimer complex and its influence on the reaction rate.

Key words: covalent drug binding, drug discovery, glutathione, glutathione conjugates, glutathione transferases, structure-activity relationships