1. Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53-MDM2 interaction. Part 1
- Author
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Weisi Wang, Lei Zhang, Yongzhou Hu, Chunqi Hu, Ni Qiu, and Shihao Shangguan
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Thiophenes ,Biochemistry ,Sensitivity and Specificity ,P53 mdm2 ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,P53 status ,Structure–activity relationship ,Humans ,Molecular Biology ,Biological evaluation ,Cell Proliferation ,Organic Chemistry ,Proto-Oncogene Proteins c-mdm2 ,Combinatorial chemistry ,Molecular Docking Simulation ,Kinetics ,chemistry ,Design synthesis ,Cell culture ,Drug Design ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Tumor Suppressor Protein p53 ,Selectivity ,Lead compound ,Protein Binding - Abstract
A series of 3,4,5-trisubstituted aminothiophenes were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory potency and anti-proliferation activities against A549 and PC3 tumor cell lines. Fourteen compounds had appreciably improved MDM2 binding affinities than lead compound MCL0527 (3) and a few compounds showed comparable activities to that of Nutlin-3. Meanwhile, most of the 3,4,5-trisubstituted aminothiophenes displayed better or equivalent anti-proliferation activities against wild-type p53 cell line A549 compared to that of Nutlin-3. Over ten compounds exhibited desirable selective profiles of p53 status. Particularly, compounds 9, 16 and 18 displayed 22-, 6- and 22-fold selectivity of p53 status, respectively, much better than that of Nutlin-3 (fourfold).
- Published
- 2013