2. Academic Validation
  3. Structure-based design, synthesis and biological evaluation of diphenylmethylamine derivatives as novel Akt1 inhibitors

Structure-based design, synthesis and biological evaluation of diphenylmethylamine derivatives as novel Akt1 inhibitors

  • Eur J Med Chem. 2014 Feb 12:73:167-76. doi: 10.1016/j.ejmech.2013.11.036.
Tao Liu 1,  Wenhu Zhan 1,  Yanming Wang 1,  Liangren Zhang 2,  Bo Yang 3,  Xiaowu Dong 4,  Yongzhou Hu 5
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China.
  • 3 Department of Pharmacology, Zhejiang University, Hangzhou 310058, China.
  • 4 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: dongxw@zju.edu.cn.
  • 5 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.
PMID: 24389511 DOI: 10.1016/j.ejmech.2013.11.036
Abstract

A series of diphenylmethylamine derivatives were rationally designed, synthesized and biologically evaluated. Most of them exhibited moderate to good Akt1 inhibitory activities, as well as promising anti-proliferative efficacy against Cancer cell lines. Besides, molecular docking studies were carried out to probe their binding modes with Akt1. Further kinase selectivity studies of compound 22c were performed, indicating its excellent selectivity against Aurora A, Drak, IKKβ, GSK3β, Syk and JAK2, and moderate selectivity against PKC and BRaf. Finally, a refined pharmacophore model was generated using the most active compounds 2, 12c and 22c via application of HipHop program.

Keywords

Akt1 inhibitor; Anti-proliferative activity; Diphenylmethylamine; Molecular docking; Pharmacophore.

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