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

Jianjun Yu; Jieyu Liu; Daqiang Li; Lei Xu; Duidui Hong; Shan Chang; Lei Xu; Jia Li; Tao Liu; Yubo Zhou

doi:10.1016/j.ejmech.2018.12.072

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. Epub 2018 Dec 31.

Authors

Jianjun Yu¹, Jieyu Liu², Daqiang Li³, Lei Xu⁴, Duidui Hong³, Shan Chang⁵, Lei Xu⁵, Jia Li², Tao Liu⁶, Yubo Zhou⁷

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: [email protected].
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: [email protected].

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, β_1c, β_2c,β_1i,β_2i > 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.

MeSH terms

Amides
Cell Line
Cell Proliferation / drug effects
Dipeptides
Drug Design*
Humans
Inhibitory Concentration 50
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology*
Microsomes, Liver / metabolism
Proteasome Inhibitors / chemistry*

Substances

Amides
Dipeptides
Macrocyclic Compounds
Proteasome Inhibitors