Design, synthesis, and biological evaluation of novel phenol ether derivatives as non-covalent proteasome inhibitors

  • Eur J Med Chem. 2019 Jan 1:161:543-558. doi: 10.1016/j.ejmech.2018.10.056.
Jianjun Yu  1 ,  Lei Xu  2 ,  Duidui Hong  1 ,  Xiaotuan Zhang  3 ,  Jieyu Liu  3 ,  Daqiang Li  1 ,  Jia Li  3 ,  Yubo Zhou  4 ,  Tao Liu  5
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, PR China.
  • 2. 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, Graduate School, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 3. 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, Graduate School, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 4. 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, Graduate School, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: [email protected].
  • 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, PR China. Electronic address: [email protected].
PMID: 30391816 DOI: 10.1016/j.ejmech.2018.10.056
Abstract

A series of novel phenol ether derivatives were designed, synthesized, and evaluated as non-covalent Proteasome inhibitors. Most compounds exhibited moderate to excellent Proteasome inhibitory activity. In particular, compound 18x proved to be the most potent compound (chymotrypsin-like: IC50 = 49 nM), exhibiting a 2-fold higher potency compared to the reported PI-1840. Besides, compound 18x exhibited excellent metabolic stability and selective anti-proliferative activity against solid Cancer cell lines including HepG2 and HGC27, providing incentive for the further development as a potential Anticancer agent against solid cancers.

Keywords
Non-covalent; Non-peptide; Phenol ether; Proteasome inhibitor; Solid cancers.