title: Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors.
abstract: A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC(50) values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC(50)=0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC(50)=4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q(2)=0.645, r(2)=0.979).
authors.affiliation: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Chunqi
authors.initials: C
authors.lastname: Hu
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Dou
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D048288:Imidazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D048288:Imidazolines; D010879:Piperazines; C482203:nutlin 1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2