Identification of 1,4-Benzodiazepine-2,5-dione Derivatives as Potential Protein Synthesis Inhibitors with Highly Potent Anticancer Activity

Abstract

In this study, a random multiple human tumor cell line screening of an in-stock small-molecule chemical library was performed, and a hit compound, 1,4-benzodiazepine-2,5-dione (BZD, <b>11a</b>; average 50% growth inhibitory concentration (GI₅₀ = 0.24 μM)) to 60 tumor cell lines of nine types of human cancers, was identified. Subsequent structure-activity relationship (SAR) investigation disclosed a highly potent antitumor compound, <b>52b</b>, that was shown to exert promising effects against lung cancer cells by inducing cell cycle arrest and apoptosis. Further polysome profile analysis revealed that <b>52b</b> inhibited protein synthesis in cancer cells. Moreover, <b>52b</b> significantly prevented tumor growth in a human non-small-cell lung cancer (NCI-H522) xenograft mouse model with no observable toxic effects. These findings are the first report of the synthetic compound <b>52b</b> with a 1,4-benzodiazepine-2,5-dione skeleton that acts as a potential protein synthesis inhibitor to effectively inhibit tumor growth.