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学科主题: 药学
题名:
Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors
作者: Zhu, Yongqiang; Yao, Shuyang; Xu, Bo; Ge, Zemei; Cui, Jingrong; Cheng, Tieming; Li, Runtao
关键词: Proteasome inhibitor ; Tripeptide boronic acid ; Drug design ; Synthesis
刊名: BIOORGANIC & MEDICINAL CHEMISTRY
发表日期: 2009-10-01
DOI: 10.1016/j.bmc.2009.08.023
卷: 17, 期:19, 页:6851-6861
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
研究领域[WOS]: Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
关键词[WOS]: 20S PROTEASOME ; CRYSTAL-STRUCTURE ; ESTERS ; PROTEIN ; PATHWAY ; HOMOLOGATION ; DEGRADATION ; BORTEZOMIB ; RESOLUTION ; PEPTIDES
英文摘要:

A series of tripeptide boronate proteasome inhibitors were designed and synthesized on the basis of our previously built tripeptide aldehyde 3D-QSAR models. All the synthesized compounds were evaluated for their proteasome-inhibitory activities in an isolated 20S rabbit proteasome, and selected compounds were evaluated for their antitumor activities in vitro against four human cancer cell lines. Biological results showed bulky and negative substituents at P(2) position improved the proteasome-inhibitory potency obviously, which completely conformed to the theoretical models, while those at P(3) position thoroughly deviated from the 3D-QSAR model. Most of the screened compounds showed less than 1 nM inhibitory potency and high selectivity against 20S proteasome, of which 7f is the most potent (IC(50) = 0.079 nM) and twofold more active than bortezomib (IC(50) = 0.161 nM). Cell viability indicated hydrophilic 4-hydroxyphenyl substituent at P(2) or P(3) position was not favorable to the cellular activities. Especially for the two hematologic cancer cell lines, HL-60 and U266, 7f inhibited them at the level of less than 10 nM and was more potent than the control bortezomib. It is being considered a promising new lead to be developed for the treatment of various cancers. (C) 2009 Elsevier Ltd. All rights reserved.

语种: 英语
所属项目编号: 30772626
项目资助者: Natural Science Foundation of China (NSFC)
WOS记录号: WOS:000269724600008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/67475
Appears in Collections:北京大学药学院_期刊论文

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作者单位: Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

Recommended Citation:
Zhu, Yongqiang,Yao, Shuyang,Xu, Bo,et al. Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2009,17(19):6851-6861.
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