School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Eur J Med Chem. 2011 Nov;46(11):5654-61. doi: 10.1016/j.ejmech.2011.09.043. Epub 2011 Oct 2.
A series of thio-benzodiazepine p53-MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (K(i) = 0.52μM) and 8f (K(i) = 0.32 μM) showed binding activity comparable to the positive drug nutlin-3a (K(i) = 0.23 μM). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC(50) value of 1.06 μM, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53-MDM2 interaction.
基于生物等排原理，设计并合成了一系列硫代苯并二氮䓬类 p53-MDM2 抑制剂。大多数硫代苯并二氮䓬类化合物对 MDM2 的亲和力为纳摩尔至微摩尔级。特别是化合物 8a（K(i) = 0.52μM）和 8f（K(i) = 0.32 μM）与阳性药物 nutlin-3a（K(i) = 0.23 μM）具有相当的结合活性。同时，化合物 8j 对 U-2 OS 人骨肉瘤细胞系表现出优异的抗肿瘤活性，IC(50)值为 1.06 μM，约为 nutlin-3a 的 23 倍。对接模型还成功预测了该类化合物模拟了三个 p53 关键残基与 MDM2 的结合。硫代苯并二氮䓬类化合物代表了一类很有前途的 p53-MDM2 相互作用的非肽抑制剂。
