期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 -, 页码 10-16出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.08.003
关键词
p53-MDM2; Thio-benzodiazepine; SAR; Antitumor activity
资金
- Key Project of Science and Technology of Shanghai [09431901700]
- Major Special Project for the Creation of New Drugs [2009ZX09301-011]
- 863 Hi-Tech Program of China [2012AA020302]
- Shanghai Rising-Star Program [12QH1402600]
- Shanghai Municipal Health Bureau [XYQ2011038]
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 (K-i = 91 nM) and 8n (K-i = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (K-i = 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. (c) 2012 Elsevier Masson SAS. All rights reserved.
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