Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

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• 作者：Chi Zhang^a ; ^c ; ¹ ; Xin Wang^b ; ^d ; ¹ ; Hongchun Liu^b ; Minmin Zhang^b ; Meiyu Geng^b ; Liping Sun^a ; ^{chslp@cpu.edu.cn} ; Aijun Shen^b ; ^{shenaj@simm.ac.cn} ; Ao Zhang^c ; ^{aozhang@simm.ac.cn}
• 关键词：Diarylisoxazole ; Resorcinol ; Amino acid ; Hsp90 inhibitor ; Antiproliferative effect
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：5 January 2017
• 年：2017
• 卷：125
• 期：Complete
• 页码：315-326
• 全文大小：2173 K
• 卷排序：125

文摘

A structure-based optimization was conducted on the clinical Hsp90 inhibitor 3. Amino acid derivatives were incorporated to the 3-amido motif of isoxazole core. 14j showed high Hsp90 binding potency and cell antiproliferative effects. 14j degradated the client protein ALK and up-regulated Hsp70. 14j formed additional apolar and polar interaction network in the ATP binding pocket of Hsp90.