Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53–MDM2 protein–protein interaction

A series of thio-benzodiazepine p53–MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (Ki = 0.52μM) and 8f (Ki = 0.32μM) showed binding activity comparable to the positive drug nutlin-3a (Ki = 0.23μM). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 1.06μM, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53–MDM2 interaction. A series of thio-benzodiazepine p53–MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines showed high inhibitory activity. [Display omitted] ▸ Thio-benzodiazepines were designed and synthesized. ▸ Most compounds showed good antitumor activity and binding affinity. ▸ We proposed a binding model for the thio-benzodiazepine–MDM2 complex.