2-((4-磺胺基苯基)氨基吡咯[2,3-d]嘧啶衍生物CDK抑制剂的设计、合成及生物学评价。

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bo Yang, Yanni Quan, Wuli Zhao, Yingjie Ji, Xiaotang Yang, Jianrui Li, Yi Li, Xiujun Liu, Ying Wang, Yanping Li
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引用次数: 2

摘要

为了探索CDK抑制剂在胰腺导管腺癌(PDAC)治疗中的潜在用途,设计、合成了一系列新型的2-(4-氨磺酰基苯基)氨基)-吡咯并[2,3-d]嘧啶衍生物,并研究了其对CDK激酶活性和癌症细胞增殖的抑制作用。大多数新的含磺酰胺衍生物在细胞培养中对CDK9具有较强的抑制活性和明显的抗增殖活性。此外,两种新化合物抑制了多种人胰腺癌症细胞系的细胞增殖。最有效的化合物2g通过阻断Rb磷酸化抑制癌症细胞增殖,并通过下调MIA-PaCa-2细胞中CDK9下游蛋白Mcl-1和c-Myc诱导细胞凋亡。CDK9敲除实验表明其抗增殖活性主要由CDK9介导。此外,2g在AsPC-1衍生的异种移植物小鼠模型中显示出中等的肿瘤抑制作用。总之,这项研究为进一步优化开发单独或联合使用PDAC治疗的潜在CDK抑制剂候选物提供了一个新的开端。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors.

Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors.

Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors.

Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors.

To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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