title: Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors.
abstract: A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC50values lower than 10 nM. Subsequently, the most potent 10 analogues were tested for their cytotoxic activities against two multiple myeloma (MM) cell lines RPMI-8226 and MM-1S. Based on these experiments, selected derivatives were further evaluated for their ex vivo and in vivo blood cell proteasome inhibitory activities. The most potential compound 35 (proteasome inhibition IC50: 1.2 ± 0.1 nM) with potent anti-proliferation (IC50: RPMI-8226 8.4 ± 0.8 nM; MM-1S: 6.3 ± 0.8 nM), ex vivo and in vivo activities also had a prolonged half life in plasma, which demonstrated that the enzymatic stabilities of this series of compounds have been improved by constructing a six-membered ring into the peptide skeleton. All the experiments confirmed the correctness of design concept, which made this series of compounds potential leads for exploring new anti-MM drugs.
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
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.
authors.forename: Lixin
authors.initials: L
authors.lastname: Gao
authors.affiliation: College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang Province, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lv
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: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: He
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: Xiaobei
authors.initials: X
authors.lastname: Hu
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: Xuwang
authors.initials: X
authors.lastname: Pan
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.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Huang
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
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China. Electronic address: zjk0125@yeah.net.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D010879:Piperazines; D010880:Piperidines; D061988:Proteasome Inhibitors; C032727:piperidine; D046988:Proteasome Endopeptidase Complex
keywords: Anti-cancer; Non-covalent; Peptidyl derivatives; Piperazine or piperidine; Proteasome inhibitors