Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors
Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors
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DOI：
10.1016/j.ejmech.2012.08.003
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发表时间：
2012-10-01
影响因子：
6.7
通讯作者：
Zhang, Wannian
中科院分区：
文献类型：
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作者：
Guo, Zizhao;Zhuang, Chunlin;Zhang, Wannian
为了探讨具有抗p53-MDM 2蛋白质相互作用活性的硫代苯并二氮杂卓类化合物的构效关系（SAR），我们设计并合成了20个苯环上带有亲电和亲核基团的化合物。其中，化合物8i（Ki = 91 nM）和8 n（Ki = 89 nM）显示出比参比药物Nutlin-3a（Ki = 121 nM）更好的结合活性。采用MTT法测定了其对Saos-2、U-2 OS、A549和NCI-H1299细胞株的体外抗肿瘤活性。特别是化合物8i和8 n具有与Nutlin-3a相当的生物活性和良好的选择性，是有希望进行进一步评价的候选化合物。(c)2012年Elsevier Masson SAS。All rights reserved.
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.