title: Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors.
abstract: A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 μM, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia 750004, China. zlyu1013@163.com.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. zclnathan@163.com.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. wuyuelin517@hotmail.com.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. guozizhao@126.com.
authors.forename: Zizhao
authors.initials: Z
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. 13601689584@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. dgq-81@163.com.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. yaojz@sh163.net.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. shengcq@hotmail.com.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. miaozhenyuan@hotmail.com.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia 750004, China. zhangwnk@hotmail.com.
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; 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; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013424:Sulfanilamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D013424:Sulfanilamides; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; D051736:Proto-Oncogene Proteins c-mdm2