Abstract

In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC₅₀ = 0.16–34.13 μM). The drug-likeness study revealed that all the new compounds conform to Lipinski’s rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G₁ phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC₅₀ = 25.53–115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents.

摘要

在当前的研究中，对带有尿素/硫脲部分的1302个吡咯嗪的小文库进行了虚拟筛选。合成得分最高的命中并评估其对三种癌细胞（MCF-7，A2780和HT29）和一种正常细胞（MRC-5）的细胞毒性。MTT分析的结果表明，大多数新化合物具有强大的细胞毒活性（IC ₅₀ = 0.16–34.13μM）。药物相似性研究表明，所有新化合物均符合Lipinski规则。化合物18b，19a和20a的机理研究表明，MCF-7细胞在G ₁期诱导了细胞凋亡和细胞周期停滞。这三种化合物还显示出对CDK-2（IC₅₀ = 25.53–115.30 nM）。此外，对接研究表明化合物19a非常适合CDK-2 / 6/9的活性位点。这些初步结果表明，化合物19a可以作为发现新的有效抗癌剂的有前途的支架。