Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors

Publication date: Available online 6 October 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Jiankang Zhang, Lixin Gao, Jianjun Xi, Li Sheng, Yanmei Zhao, Lei Xu, Yidan Shao, Shourong Liu, Rangxiao Zhuang, Yubo Zhou, Jia Li
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4±0.1 nM) and cytotoxicities with IC50 values at 13.9±1.8 nM and 9.5±0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27-29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs.

Graphical abstract

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