Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors. Issue 23 (1st December 2016)

• Record Type: Journal Article
• Authors: Zhang, Jiankang; Gao, Lixin; Xi, Jianjun; Sheng, Li; Zhao, Yanmei; Xu, Lei; Shao, Yidan; Liu, Shourong; Zhuang, Rangxiao; Zhou, Yubo; Li, Jia
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 23(2016)
• Page Start: 6206
• Page End: 6214
• Publication Date: 2016-12-01
• Subjects: Proteasome inhibitors -- Piperidine -- Non-covalent -- Anti-cancer -- SARs; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.10.002
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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. Compound28 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 compounds24 and27 –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.