A novel lead of P-selectin inhibitor: Discovery, synthesis, bioassays and action mechanism

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• 作者：Jianhui Wu^a ; Ming Zhao^a ; ^b ; ^{mingzhao@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Yuji Wang^a ; Yaonan Wang^a ; Haimei Zhu^a ; Shurui Zhao^a ; Shiqi Peng^a ; ^{sqpeng@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：β-Carboline ; P-selectin ; Inhibitor ; Anti-thrombosis ; Anti-inflammation
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：26
• 期：19
• 页码：4631-4636
• 全文大小：1459 K

文摘

By docking 126 derivatives of β-carboline-3-carboxylic acid, tetrahydro-β-carboline-3-carboxylic acid and indoloquinolizine into the active pocket of P-selectin (2-(3-(hydroxymethyl)-9H-pyrido[3,4-b]indol-1-yl)ethyl)-l-phenylalanine (HMCEF) was assigned a novel inhibitor. ELISA and flow cytometry experiments showed that HMCEF effectively down-regulated P-selectin expression and supported the rationality of the computer assistant screening, while UV spectrum experiments demonstrated that HMCEF directly bound to P-selectin. In vivo HMCEF dose dependently inhibited the rats and mice to form thrombus and had a minimal effective dose of 20 nmol/kg, dose dependently inhibited inflammatory response of mice and had a minimal effective dose of 20 nmol/kg. The decrease of serum TNFα and IL-8 of the treated mice was proposed to be the action mechanism of HMCEF inhibiting thrombosis and inflammation. All data imply that HMCEF is a novel lead of P-selectin inhibitor.