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

Jianjun Yu; Lei Xu; Duidui Hong; Xiaotuan Zhang; Jieyu Liu; Daqiang Li; Jia Li; Yubo Zhou; Tao Liu

doi:10.1016/j.ejmech.2018.10.056

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. Epub 2018 Oct 26.

Authors

Jianjun Yu¹, Lei Xu², Duidui Hong¹, Xiaotuan Zhang³, Jieyu Liu³, Daqiang Li¹, Jia Li³, Yubo Zhou⁴, Tao Liu⁵

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Ethers / chemical synthesis
Ethers / chemistry
Ethers / pharmacology*
Humans
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Phenols / chemical synthesis
Phenols / chemistry
Phenols / pharmacology*
Proteasome Endopeptidase Complex / metabolism*
Proteasome Inhibitors / chemical synthesis
Proteasome Inhibitors / chemistry
Proteasome Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Ethers
Phenols
Proteasome Inhibitors
Proteasome Endopeptidase Complex