1,3-Dibenzyl-2-Aryl Imidazolines As Novel Hsp 90 Inhibitors:Identification And Structure-Activity Relationship Study

Hsp90 is involved in various processes of occurrence and development of cancers.Hsp90 could maintain the survival of tumor cells and inhibit their apoptosis.Therefore,Hsp90 is an important drug target for cancer therapy.Developing effective Hsp90 inhibitors is considered as an effective strategy in the treatment of cancers.This thesis is expected to develop novel Hsp90 inhibitors possessing high efficiency and low toxicity through structure based virtual screening and structural optimization.First,using Hsp90 as target,virtual screening was employed to screen a molecular library containing 300,000 molecules.The molecules were screened by RO5 rules and followed by molecule docking.21 compounds were selected for anti-tumor activity evaluation using MCF-7 cell line and 1,3-dibenzyl-2-aryl-imidazoline was used as a lead compound for structure-activity relationship study.Then,a series of derivatives were designed with 2-aryl-imidazoline as the core skeleton.The synthesis was achieved by the reactions of substituting ethylenediamines and aldehydes.22 compounds were synthesized.The antiproliferative activity of these imidazolidines were evaluated against MCF-7 and A549 cells lines using MTT assay.Compound 4a exhibited the strongest anti-proliferative activity against MCF-7 and A549 cell lines with IC₅₀0 values of21.58μM and 31.22μM,respectively.Structure-activity relationship study revealed that N-benzyl plays a crucial role in the anti-tumor activity of 1,3-dibenzyl-2-aryl imidazoline.When the benzyl group at the 1,3 position of the imidazoline is substituted with a smaller group such as a phenyl group,a methyl group and an ethyl group,the antiproliferative activity of the compound is remarkably reduced.Finally,the inhibitory effect of this kind of compounds on Hsp90were studied by western blotting assay.1,3-dibenzyl-2-aryl imidazoline could significantly down-regulate the expression level of Her2,which paralleled with the cytotoxicity.Additionally,molecular docking were performed and the result showed 1,3-dibenzyl-2-aryl-imidazoline could competitively bind to ATP binding site at the end of Hsp90 N terminus,inhibiting the ATPase activity of Hsp90.