Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure−Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of β-A
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- 作者：Yongqiang Zhu ; Xinrong Zhu ; Gang Wu ; Yuheng Ma ; Yuejie Li ; Xin Zhao ; Yunxia Yuan ; Jie Yang ; Sen Yu ; Feng Shao ; Runtao Li ; Yanrong Ke ; Aijun Lu ; Zhenming Liu ; Liangren Zhang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：March 11, 2010
- 年：2010
- 卷：53
- 期：5
- 页码：1990-1999
- 全文大小：943K
- 年卷期：v.53,no.5(March 11, 2010)
- ISSN：1520-4804
文摘
A series of novel dipeptidyl boronic acid proteasome inhibitors composed of β-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 was 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 as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC50 values nearly less than 5 μM 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 a similar way as bortezomib.