Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, PR China.
Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China.
Eur J Med Chem. 2018 Feb 10;145:551-558. doi: 10.1016/j.ejmech.2018.01.024. Epub 2018 Jan 10.
Heat shock protein 90 (HSP90) inhibition has aroused increasing enthusiasm in antitumor strategies in recent years. According to our previous studies, we synthesized a series of coumarin pyrazoline compounds HCP1-HCP6 that might be HSP90 inhibitors. Interactions between HCP1-HCP6 and HSP90 were examined and antitumor activities of them were investigated in A549 lung cancer cells. Results showed that all the six derivatives could interact with HSP90, in which HCP1 exhibited the best binding ability and inhibited the activity of HSP90. Meanwhile, HCP1-HCP6 reduced the cell viability of A549 cells and HCP1 possessed the lowest IC value. Above all HCP1 exerted better HSP90 inhibitory and anticancer effects than our initially identified HSP90 inhibitor DPB. As to the underlying mechanism, HCP1-HCP6 not only induced apoptosis as DPB but also blocked autophagic flux in A549 cells. Therefore, we discovered a novel HSP90 inhibitor HCP1 that had better biological activity and provided us a useful tool to explore the underlying mechanism of lung cancer therapy.
近年来，热休克蛋白 90（HSP90）抑制在抗肿瘤策略中引起了越来越多的关注。根据我们之前的研究，我们合成了一系列可能是 HSP90 抑制剂的香豆素吡唑啉化合物 HCP1-HCP6。我们研究了 HCP1-HCP6 与 HSP90 之间的相互作用，并在 A549 肺癌细胞中研究了它们的抗肿瘤活性。结果表明，所有这六个衍生物都可以与 HSP90 相互作用，其中 HCP1 表现出最好的结合能力并抑制 HSP90 的活性。同时，HCP1-HCP6 降低了 A549 细胞的活力，而 HCP1 具有最低的 IC 值。总之，HCP1 对 HSP90 的抑制作用和抗癌作用均优于我们最初鉴定的 HSP90 抑制剂 DPB。至于潜在的机制，HCP1-HCP6 不仅像 DPB 一样诱导细胞凋亡，还阻断了 A549 细胞中的自噬流。因此，我们发现了一种新型的 HSP90 抑制剂 HCP1，它具有更好的生物学活性，为我们提供了一个有用的工具来探索肺癌治疗的潜在机制。
