Design and synthesis of substituted pyrido[3,2-d]-1,2,3-triazines as potential Pim-1 inhibitors

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• 作者：Yin-Bo Fan^a ; Kun Li^a ; Min Huang^a ; Yu Cao^a ; Ying Li^b ; Shu-Yu Jin^a ; Wen-Bing Liu^a ; Jia-Chen Wen^a ; Dan Liu^a ; ^{sammyld@163.com" class="auth_mail" title="E-mail the corresponding author} ; Lin-Xiang Zhao^a ; ^{linxiang.zhao@vip.sina.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pim-1 kinase inhibitors ; Pyrido[3 ; 2-d]-1 ; 2 ; 3-triazines ; Anti-proliferative activity ; Prostate cancer cells
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：26
• 期：4
• 页码：1224-1228
• 全文大小：1028 K

文摘

A novel series of substituted pyrido[3,2-d]-1,2,3-triazines were designed and synthesized as Pim-1 inhibitors through scaffold hopping. Most of the derivatives showed potent in vitro Pim-1 inhibitory activities and anti-proliferative effects toward prostate cancer cells. Among them, trong class="boldFont">6btrong>, trong class="boldFont">6htrong> and trong class="boldFont">6mtrong> showed the best Pim-1 inhibitory activity with IC₅₀ values of 0.69, 0.60 and 0.80 μM, respectively. Furthermore, compounds trong class="boldFont">6btrong>, trong class="boldFont">6itrong>, trong class="boldFont">6jtrong> and trong class="boldFont">6mtrong> showed strong inhibitory activity to human prostate cancer LNcap and PC-3 cell lines with IC₅₀ values at low micromolar level. Structure–activity relationship analysis revealed that appropriate substitutions at C-6 positions contributed to the kinase inhibition and antiproliferative effects. Moreover, western blot assay suggested that trong class="boldFont">6jtrong> could decrease the levels of p-BAD and p-4E-BP1 in a dose-dependent manner in PC-3 cells. Docking studies showed that 3-N of the scaffold formed a hydrogen bond with Lys67, aromatic 4-aniline formed a key π–π stack with Phe49. Taken together, this study might provide the first sight for developing the pyrido[3,2-d]-1,2,3-triazine scaffold as novel Pim-1 inhibitors.