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Synthesis and biological evaluation of selected 7-azaindole derivatives as CDK9/Cyclin T and Haspin inhibitors
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2020-05-22 , DOI: 10.1007/s00044-020-02560-1
Lianie Pieterse , Lesetja J. Legoabe , Richard M. Beteck , Béatrice Josselin , Stéphane Bach , Sandrine Ruchaud

The 7-azaindole scaffold attracts attention due to its value in the design of inhibitors of diseases related protein kinases. However, this scaffold has not been evaluated against Haploid germ cell-specific nuclear protein kinase (Haspin). Herein, we report the synthesis of a select set of 7-azaindole derivatives and their evaluation against Haspin. The compounds were also evaluated against CDK9/Cyclin T kinase. The synthesis of 7-azaindole derivatives was achieved through Suzuki coupling using appropriate halogenated 7-azaindole and boronic acids. Seven of the screened compounds exhibited activity as CDK9/Cyclin T and/or Haspin inhibitors in a nanomolar to low micromolar range. The most promising dual inhibiting compound 18c, exhibited an inhibitory potential of 0.206 µM against CDK9/Cyclin T and 0.118 µM against Haspin. The dual inhibition of CDK9/Cyclin T and Haspin could afford a potentially potent antimitotic agent of value in further anticancer studies.

中文翻译:

选定的7-氮杂吲哚衍生物作为CDK9 / Cyclin T和Haspin抑制剂的合成及生物学评估

7-氮杂吲哚支架由于其在疾病相关蛋白激酶抑制剂设计中的价值而备受关注。但是,该支架尚未针对单倍体生殖细胞特异性核蛋白激酶(Haspin)进行评估。本文中,我们报告了一组7-氮杂吲哚衍生物的合成及其对Haspin的评价。还针对CDK9 /细胞周期蛋白T激酶评估了化合物。7-氮杂吲哚衍生物的合成是通过使用适当的卤代7-氮杂吲哚和硼酸的Suzuki偶联而实现的。所筛选的化合物中的七个在纳摩尔至低微摩尔范围内表现出作为CDK9 / Cyclin T和/或Haspin抑制剂的活性。最有前途的双重抑制化合物18c对CDK9 / Cyclin T的抑制潜力为0.206 µM,对Haspin的抑制潜力为0.118 µM。CDK9 /细胞周期蛋白T和Haspin的双重抑制可提供潜在的潜在抗有丝分裂剂,在进一步的抗癌研究中具有价值。
更新日期:2020-05-22
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