title: Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction.
abstract: 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.
authors: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors: Chunlin
authors: C
authors: Zhuang
authors: Zhenyuan
authors: Z
authors: Miao
authors: Lingjian
authors: L
authors: Zhu
authors: Yongqiang
authors: Y
authors: Zhang
authors: Zizhao
authors: Z
authors: Guo
authors: Jianzhong
authors: J
authors: Yao
authors: Guoqiang
authors: G
authors: Dong
authors: Shengzheng
authors: S
authors: Wang
authors: Yang
authors: Y
authors: Liu
authors: Hai
authors: H
authors: Chen
authors: Chunquan
authors: C
authors: Sheng
authors: Wannian
authors: W
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; D013455:Sulfur; D051736:Proto-Oncogene Proteins c-mdm2