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Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors
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
2009-10-01
DOI10.1016/j.bmc.2009.08.023
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
WOS记录号WOS:000269724600008
项目编号30772626
资助机构Natural Science Foundation of China (NSFC)
引用统计
被引频次:25[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67475
专题北京大学药学院
北京大学药学院_化学生物学系
北京大学药学院_分子与细胞药理学系
北京大学临床肿瘤学院_肿瘤放疗科
作者单位Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
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GB/T 7714
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.
APA Zhu, Yongqiang.,Yao, Shuyang.,Xu, Bo.,Ge, Zemei.,Cui, Jingrong.,...&Li, Runtao.(2009).Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,17(19),6851-6861.
MLA Zhu, Yongqiang,et al."Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 17.19(2009):6851-6861.
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