Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Bioorg Chem. 2021 Oct;115:105220. doi: 10.1016/j.bioorg.2021.105220. Epub 2021 Jul 29.
Two series of 2,7-diaryl-pyrazolo[1,5-a]pyrimidines as tubulin polymerization inhibitors were designed to restrict bioactive configuration of (E,Z)-vinylogous CA-4. All of the target compounds were synthesized and then evaluated for their in vitro antiproliferative activities against three cancer cell lines (MCF-7, SGC-7901 and A549). Among them, 6d exhibited the most potent antiproliferative activity against the MCF-7 with IC value of 0.047 μM. Moreover, 6d significantly inhibited tubulin polymerization, disrupted microtubule networks, arrested cell cycle at G2/M phase, induced apoptosis and hindered cancer cell migration. Colchicine competition assay and molecular docking studies suggested that 6d could interact with tubulin by binding to the colchicine site.
设计了两个系列的 2,7-二芳基-吡唑并[1,5-a]嘧啶作为微管聚合抑制剂，以限制（E,Z）-乙烯基 CA-4 的生物活性构象。所有目标化合物均已合成，并对其体外抗三种癌细胞系（MCF-7、SGC-7901 和 A549）的增殖活性进行了评估。其中，化合物 6d 对 MCF-7 的抑制活性最强，IC 值为 0.047 μM。此外，化合物 6d 还能显著抑制微管聚合、破坏微管网络、将细胞周期阻滞在 G2/M 期、诱导细胞凋亡和抑制癌细胞迁移。秋水仙碱竞争实验和分子对接研究表明，化合物 6d 可以通过与秋水仙碱结合位点结合来与微管相互作用。
