Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI:10.1016/j.bmcl.2025.130260

Meixue Ai , Yukang Lin , Xiaoyu Zhong , Zhongkai Zou , Pengcheng Diao , Yanting Zhang , Jingkao Chen , Peiliang Zhao , Zhibo Zhu

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Abstract

PLK1 plays a pivotal role in cell-cycle regulation and has been well-characterized as a promising target for cancer therapy. Here, we synthesized a series of fused-thiophene based aminopyrimidine derivatives, and discovered a novel and potent PLK1 inhibitor compound 7n with an IC₅₀ value of 38.5 nM. Analogue 7n exhibited remarkable antiproliferative efficacy toward HepG2, Huh7, H1299, and A549 cells, and hasn't any noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies indicated 7n arrested the cell cycle at the G2/M phase and induced apoptosis in HepG2 cells with a concentration-dependent manner. Molecular docking presented that 7n could occupy well the ATP-binding site of PLK1 with a U-shaped conformation. Collectively, these results provide new insights into the further development of fused-thiophene based aminopyrimidines as PLK1 inhibitors.

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新型环烷基噻吩基氨基嘧啶衍生物作为PLK1抑制剂的设计、合成和评价

PLK1在细胞周期调控中起着关键作用，被认为是癌症治疗的一个有希望的靶点。在此，我们合成了一系列基于噻吩的融合氨基嘧啶衍生物，并发现了一种新的有效的PLK1抑制剂化合物7n， IC50值为38.5 nM。类似物7n对HepG2、Huh7、H1299和A549细胞有明显的抗增殖作用，对非肿瘤细胞系HEK-293细胞无明显的细胞毒活性。进一步的机制研究表明，7n在G2/M期阻滞细胞周期，并以浓度依赖性方式诱导HepG2细胞凋亡。分子对接表明，7n可以很好地占据PLK1的u型构象的atp结合位点。总的来说，这些结果为进一步开发基于噻吩的融合氨基嘧啶作为PLK1抑制剂提供了新的见解。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.