2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents

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.

Aconitine; Antiproliferative activity; Hsp90 inhibitors; Structural simplification.