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Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors.

Abstract：

:A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti-proliferation activities against three multiple myeloma (MM) cell lines. 8 analogues displayed more potent activities than carfilzomib, and the most promising compound 24 showed IC50 values of 0.8 ± 0.2 nM against 20S proteasome and 8.42 ± 0.74 nM, 7.14 ± 0.52 nM, 14.20 ± 1.08 nM for RPMI 8226, NCI-H929 and MM.1S cell lines, respectively. Additionally, mechanisms of anti-cancer activity of representative compound 24 were further investigated. Apoptosis of RPMI-8226 cells were achieved through accumulating polyubiquitin and inducing the cleavage of caspase and PARP. Besides, half-life in rat plasma of compound 24 was prolonged after optimization, which would be helpful for increasing in vivo activities of this series of derivatives. All the studies confirmed that piperidine-containing non-covalent proteasome inhibitors can be potential leads for anti-MM drug development.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Zhao Y,Xu L,Zhang J,Zhang M,Lu J,He R,Xi J,Zhuang R,Li J,Zhou Y

doi

10.1016/j.bmc.2020.115867

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

115867

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30697-0

journal_volume

29

pub_type

杂志文章

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