Development of FTase inhibitors inspired by the structures of andrastins

We designed and synthesized structurally simple farnesyl transferase (FTase) inhibitors ( 1a – 1d ) by leveraging andrastin, a natural product with FTase inhibitory activity. 1a – 1d possess a cyclopentane-1,3-dione core, which is critical for FTase recognition; a farnesyl moiety, which is a simplified motif of A to C rings of andrastin; and a carboxylic acid or methoxycarbonyl group, which enables multipoint hydrogen bonding interactions with FTase. Competitive inhibition experiments revealed that 1d has the most potent FTase inhibitory activity. Docking simulation analysis of 1a – 1d with FTase suggested that the multipoint hydrogen bonding interactions between the cyclopentane-1,3-dione moiety and the carboxyl group play an important role in FTase recognition.