title: Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors.
abstract: 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.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Zizhao
authors.initials: Z
authors.lastname: Guo
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Lingjian
authors.initials: L
authors.lastname: Zhu
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Shengzheng
authors.initials: S
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Hai
authors.initials: H
authors.lastname: Chen
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Wannian
authors.initials: W
authors.lastname: 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; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D013438:Sulfhydryl Compounds; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2