The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC₅₀ value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC₅₀ value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model.

分子伴侣热激蛋白90（Hsp90）是癌症治疗的有希望的目标。天然产物乌头碱是我们先前工作中报道的潜在Hsp90抑制剂。在这项研究中，我们设计和合成了一系列的2-（（1-苯基-1 H -1,2,3-三唑-4-基）甲基）-2-氮杂双环[3.2.1] octan-3-one通过简化和修饰乌头碱支架，将其衍生物作为有效的Hsp90抑制剂。在这些化合物中，14t对LoVo细胞表现出优异的抗增殖活性，IC ₅₀值为0.02μM，Hsp90α抑制活性很强，IC ₅₀值为0.71 nM。分子对接研究提供了14t的合理结合模型与Hsp90α复合。随后的细胞周期和凋亡测定表明，化合物14t可以通过上调bax和半胱天冬酶3的表达，同时抑制bcl-2的表达，从而使细胞周期停留在G1 / S期并诱导细胞凋亡。而且，14t可以抑制LoVo和SW620细胞系中的细胞迁移。与体外结果一致，在SW620异种移植小鼠模型中14t显着抑制了肿瘤的生长。