2. Academic Validation
  3. Exploration of novel macrocyclic dipeptide N-benzyl amides as proteasome inhibitors

Exploration of novel macrocyclic dipeptide N-benzyl amides as proteasome inhibitors

  • Eur J Med Chem. 2019 Feb 15:164:423-439. doi: 10.1016/j.ejmech.2018.12.072.
Jianjun Yu 1,  Jieyu Liu 2,  Daqiang Li 3,  Lei Xu 4,  Duidui Hong 3,  Shan Chang 5,  Lei Xu 5,  Jia Li 2,  Tao Liu 6,  Yubo Zhou 7
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, Zhejiang, 310058, PR China; School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, PR China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 3 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201203, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 5 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, PR China.
  • 6 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China. Electronic address: Lt601@zju.edu.cn.
  • 7 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: ybzhou@simm.ac.cn.
PMID: 30611983 DOI: 10.1016/j.ejmech.2018.12.072
Abstract

As Proteasome inhibitors, a series of novel macrocyclic dipeptide N-benzyl amides were designed, synthesized and evaluated. Most of them exhibited potent Proteasome inhibition and excellent anti-proliferative activity against RPMI 8226, MM1S, and MV-4-11 cell lines. As the most distinguished one among this series, compound 23h displayed potent and selective Proteasome inhibitory potency (IC50: β5c = 29 nM, β5i = 35 nM, β1c, β2c,β1i,β2i > 10 μM), excellent anti-proliferative activity against RPMI 8226, MM1S, and MV-4-11 cell lines with IC50 values of 18 nM, 15 nM, and 21 nM, respectively, as well as favorable metabolic stability in human liver microsomes (HLMs), highlighting that it is a promising lead compound for further development of Proteasome inhibitors.

Keywords

Macrocyclic dipeptides; Metabolic stability; N-Benzyl amides; Proteasome inhibitors.

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