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

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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.