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Open AccessCommunication
Int. J. Mol. Sci. 2014, 15(9), 15741-15753; doi:10.3390/ijms150915741

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

1
School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia 750004, China
2
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 18 June 2014 / Revised: 17 July 2014 / Accepted: 18 July 2014 / Published: 5 September 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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. View Full-Text
Keywords: p53-MDM2; small molecule inhibitors; sulfamidebenzodiazepine; triazolebenzodiazepine; antitumor activity p53-MDM2; small molecule inhibitors; sulfamidebenzodiazepine; triazolebenzodiazepine; antitumor activity
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Yu, Z.; Zhuang, C.; Wu, Y.; Guo, Z.; Li, J.; Dong, G.; Yao, J.; Sheng, C.; Miao, Z.; Zhang, W. Design, Synthesis and Biological Evaluation of Sulfamide and Triazole Benzodiazepines as Novel p53-MDM2 Inhibitors. Int. J. Mol. Sci. 2014, 15, 15741-15753.

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