Design, Synthesis and Biological Evaluation of Sulfamide and Triazole Benzodiazepines as Novel p53-MDM2 Inhibitors

• Main Authors: Zhiliang Yu, Chunlin Zhuang, Yuelin Wu, Zizhao Guo, Jin Li, Guoqiang Dong, Jianzhong Yao, Chunquan Sheng, Zhenyuan Miao, Wannian Zhang
• Format: Article
• Language: English
• Published: MDPI AG 2014-09-01
• Series: International Journal of Molecular Sciences
• Subjects: p53-MDM2; small molecule inhibitors; sulfamidebenzodiazepine; triazolebenzodiazepine; antitumor activity
• Online Access: http://www.mdpi.com/1422-0067/15/9/15741

A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 μM, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.