title: Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors.
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 IC50less than 20nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4±0.1nM) and cytotoxicities with IC50values at 13.9±1.8nM and 9.5±0.5nM 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.
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Xi
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
authors.forename: Shourong
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China. Electronic address: zhuangrangxiao@sina.com.
authors.forename: Rangxiao
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ybzhou@simm.ac.cn.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D010880:Piperidines; D061988:Proteasome Inhibitors; C524865:carfilzomib; D002918:Chymotrypsin
keywords: Anti-cancer; Non-covalent; Piperidine; Proteasome inhibitors; SARs