热休克蛋白90(Hsp90)参与癌症发生发展的各种过程,因此代表了癌症治疗的有希望的药物靶标。在这项工作中,采用了虚拟筛查策略,导致鉴定出一系列具有1,3-二苄基-2-芳基咪唑烷支架的化合物作为新型Hsp90抑制剂。化合物4a在荧光偏振(FP)竞争试验中对Hsp90α具有最高的结合亲和力(IC50=12nM),对人乳腺癌细胞系(MCF-7)和人肺上皮细胞系(A549)具有最强的抗增殖活性,IC50值为21.58μM和31.22μM,分别。Western印迹分析显示,这些新型Hsp90抑制剂显著下调Hsp90的客户蛋白Her2的表达水平,导致这些新型Hsp90抑制剂的细胞毒性。分子对接研究表明,这些新型Hsp90抑制剂与Hsp90N端的三磷酸腺苷(ATP)结合位点结合。此外,构效关系研究表明,N-苄基对1,3-二苄基-2-芳基咪唑啉的抗癌活性很重要。
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.