Structure–activity relationship and antitumor activity of thio-benzodiazepines as p53–MDM2 protein–protein interaction inhibitors

In order to discuss the structure–activity relationship (SAR) of the thio-benzodiazepine compounds which showed excellent activity against p53–MDM2 protein–protein interaction, we designed and synthesized twenty compounds with electrophilic and nucleophilic groups on the benzene ring. Among them, compounds 8i (Ki = 91 nM) and 8n (Ki = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (Ki = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, compounds 8i and 8n possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation.

Further discussion of the structure–activity relationship of thio-benzodiazepines was realized in our present study. Two promising compounds 8i and 8n with excellent bioactivity were obtained.Figure optionsDownload as PowerPoint slideHighlights
► Further discussion of thio-benzodiazepines was carried out.
► Most compounds showed good antitumor activity and binding affinity.
► A preliminary structure–activity relationship was obtained.