新型 CDK9/CyclinT 和 Haspin 抑制剂的 7H-吡咯并[2,3-d]嘧啶衍生物的合成与生物评价。

Synthesis and biological evaluation of selected 7H-pyrrolo[2,3-d]pyrimidine derivatives as novel CDK9/CyclinT and Haspin inhibitors.

机构信息

Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.

Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff Cedex, France.

出版信息

Chem Biol Interact. 2021 Nov 1;349:109643. doi: 10.1016/j.cbi.2021.109643. Epub 2021 Sep 9.

DOI:10.1016/j.cbi.2021.109643

PMID:34508710

Abstract

Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesised and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC of 0.38 μM) and Haspin (IC of 0.11 μM) activities were achieved by compounds 7d and 7f, respectively. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.

摘要

蛋白激酶，包括 CDK9/细胞周期蛋白 T 和 Haspin，被认为是癌症治疗中潜在的药物靶点。先前的一项研究结果表明，7-氮茚作为一种产生 CDK9/细胞周期蛋白 T 和 Haspin 抑制剂的优势骨架。受这些发现的启发，本研究合成并评估了十三（13）个 C6 取代的 7-氮茚和二十（20）个 C4 取代的结构相关的 7H-吡咯并[2,3-d]嘧啶衍生物对一系列蛋白激酶，包括 CDK9/细胞周期蛋白 T 和 Haspin 的抑制作用。11 个 7H-吡咯并[2,3-d]嘧啶衍生物对 CDK9/细胞周期蛋白 T 具有活性，而 4 个化合物对 Haspin 具有活性。化合物 7d 和 7f 的 CDK9/细胞周期蛋白 T（IC50 为 0.38 μM）和 Haspin（IC50 为 0.11 μM）活性最好。因此，这些化合物可能是开发新型抗癌药物的有价值的起点。