Design, synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors

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• 作者：Dingding Gao ; Qiang Xiao ; Mingming Zhang ; ^{zmmworld@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Yingxia Li ; ^{liyx417@fudan.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：STAT3 ; signal transducers and activators of transcription 3 ; IL-6 ; interleukin-6 ; JAK ; Janus kinase ; SAR ; structure&ndash ; activity relationships
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：24
• 期：11
• 页码：2549-2558
• 全文大小：1272 K

文摘

STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC₅₀ values as low as 7.71 μM and 1.38 μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC₅₀ value of 9.61 μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration.