Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification.

Abstract Chaetocin ( 1 ), a structurally complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetomium minutum , is a potent inhibitor of protein lysine methyltransferase G9a, which plays important roles in many biological processes. Here we present our synthetic investigations to identify a simple prototype G9a inhibitor structure based on structure–activity relationship (SAR) studies on chaetocin derivatives. The simple derivative PS-ETP-1 ( 14 ) was found to be a potent G9a inhibitor with greatly reduced cytotoxicity.