Design, Synthesis, Biological Evaluation, and Structure−Activity Relationship (SAR) Discussion of Dipeptidyl Boronate Proteasome Inhibitors, Part I: Comprehensive Understanding of the SAR of

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• 作者：Yongqiang Zhu ; Xin Zhao ; Xinrong Zhu ; Gang Wu ; Yuejie Li ; Yuheng Ma ; Yunxia Yuan ; Jie Yang ; Yang Hu ; Li Ai ; Qingzhi Gao
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 23, 2009
• 年：2009
• 卷：52
• 期：14
• 页码：4192-4199
• 全文大小：836K
• 年卷期：v.52,no.14(July 23, 2009)
• ISSN：1520-4804

文摘

New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC₅₀ values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC₅₀ values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC₅₀ value range of 9.8−70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.