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Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure-Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of beta-Amino Acids
Zhu, Yongqiang1,2; Zhu, Xinrong1,2; Wu, Gang1,2; Ma, Yuheng1,2; Li, Yuejie1,2; Zhao, Xin1,2; Yuan, Yunxia1,2; Yang, Jie1,2; Yu, Sen1,2; Shao, Feng1,2; Li, Runtao3; Ke, Yanrong3; Lu, Aijun1,2; Liu, Zhenming3; Zhang, Laingren3
刊名JOURNAL OF MEDICINAL CHEMISTRY
2010-03-11
DOI10.1021/jm901407s
53期:5页:1990-1999
收录类别SCI ; IC
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Medicinal
资助者National Key New Drug Creation Program ; Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research Foundation ; National Key New Drug Creation Program ; Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research Foundation
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]20S PROTEASOME ; SECONDARY STRUCTURE ; CRYSTAL-STRUCTURE ; DRUG DISCOVERY ; COMSIA METHODS ; SOLID TUMORS ; ZEBRAFISH ; DESIGN ; BORTEZOMIB ; 3D-QSAR
英文摘要

A series of novel dipeptidyl boronic acid proteasome inhibitors composed of beta-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i wits the most active. The IC50 value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active its the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC50 values nearly less than 5 mu M against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in it similar way as bortezomib.

语种英语
所属项目编号2009ZX09103-001 ; BM2008201
资助者National Key New Drug Creation Program ; Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research Foundation ; National Key New Drug Creation Program ; Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research Foundation
WOS记录号WOS:000275087000009
Citation statistics
Cited Times:30[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/51115
Collection北京大学药学院
作者单位1.Jiangsu Simcere Pharmaceut Res Inst, Nanjing 210042, Peoples R China
2.Jiangsu Key Lab Mol Targeted Antitumor Drug Res, Nanjing 210042, Peoples R China
3.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
Recommended Citation
GB/T 7714
Zhu, Yongqiang,Zhu, Xinrong,Wu, Gang,et al. Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure-Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of beta-Amino Acids[J]. JOURNAL OF MEDICINAL CHEMISTRY,2010,53(5):1990-1999.
APA Zhu, Yongqiang.,Zhu, Xinrong.,Wu, Gang.,Ma, Yuheng.,Li, Yuejie.,...&Zhang, Laingren.(2010).Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure-Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of beta-Amino Acids.JOURNAL OF MEDICINAL CHEMISTRY,53(5),1990-1999.
MLA Zhu, Yongqiang,et al."Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure-Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of beta-Amino Acids".JOURNAL OF MEDICINAL CHEMISTRY 53.5(2010):1990-1999.
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