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

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, 11a; 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, 52b, that was shown to exert promising effects against lung cancer cells by inducing cell cycle arrest and apoptosis. Further polysome profile analysis revealed that 52b inhibited protein synthesis in cancer cells. Moreover, 52b 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 52b with a 1,4-benzodiazepine-2,5-dione skeleton that acts as a potential protein synthesis inhibitor to effectively inhibit tumor growth.