Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors

Molecules

Hongyu Xue¹  Xiaoxia Liu¹  Lihong Li¹  Yajun Liu¹  Yong Liu¹  Rui Dai¹  Meiyun Shi¹  Hecheng Wang¹ 

[1] School of Life Science and Medicine, Dalian University of Technology, Dagong Road No. 2, Panjin 124221, China;

关键词: Hsp90;    imidazolidine;    anti-cancer;    molecule docking;    virtual screening;   

DOI  :  10.3390/molecules24112105

来源: DOAJ

【 摘 要 】

Hsp90 (Heat shock protein 90) is involved in various processes in cancer occurrence and development, and therefore represents a promising drug target for cancer therapy. In this work, a virtual screening strategy was employed, leading to the identification of a series of compounds bearing a scaffold of 1,3-dibenzyl-2-aryl imidazolidine as novel Hsp90 inhibitors. Compound 4a showed the highest binding affinity to Hsp90α (IC₅₀ = 12 nM) in fluorescence polarization (FP) competition assay and the strongest anti-proliferative activity against human breast adenocarcinoma cell line (MCF-7) and human lung epithelial cell line (A549) with IC₅₀ values of 21.58 μM and 31.22 μM, respectively. Western blotting assays revealed that these novel Hsp90 inhibitors significantly down-regulated the expression level of Her2, a client protein of Hsp90, resulting in the cytotoxicity of these novel Hsp90 inhibitors. The molecular docking study showed that these novel Hsp90 inhibitors bound to the adenosine triphosphate (ATP) binding site at the N-terminus of Hsp90. Furthermore, structure−activity relationship studies indicated that the N-benzyl group is important for the anti-cancer activity of 1,3-dibenzyl-2-aryl imidazolidines.

【 授权许可】

Unknown