Design,Synthesis And Activity Evaluation Of Hedgehog Inhibitor Itraconazole Derivatives

Malignant tumor is one of the biggest threats to human health.The important task of treating tumor is to develop anti-cancer drugs with good curative effect,high activity and drug resistance.Studies have found that the occurrence and development of various cancers are related to the abnormal activation of Hedgehog signaling channels,such as basal cell carcinoma,non-small cell lung cancer,medulloblastoma,etc.^[1].Therefore,targeting key components of the upstream and downstream of Hedgehog signaling pathway（including SHH,Smoothened and Gli）to design targeted inhibitors has become a research hotspot.Smoothened（Smo）is the most widely targeted drug,and the three Hedgehog inhibitors currently on the market all target Smo.However,the clinical results show that drug resistance problems will occur after the use of these drugs,so it is very important to continue to develop new Hedgehog inhibitors.In this paper,a series of derivatives were designed and synthesized using Itraconazole,a phase II clinical Hedgehog signaling pathway inhibitor,as the lead product,and their activity was tested in vitro.This paper mainly includes the following contents:1.Experimental synthesis techniques for Itraconazole,the lead compound,were explored and the synthesis route for Itraconazole,the lead compound,was optimized with high yield,easy raw materials and easy operation.2.Fourteen Itraconazole derivatives were designed and synthesized using molecular simulation techniques,pharmacophore integration,bioelectron equiarrangement,and homolog derivatization.3.Biological activity of the target compound was studied.Anti-proliferation activity test and Hedgehog inhibitory activity test were conducted on the synthetic Itraconazole derivatives,and the derivatives C-7 and C-14 were found to have good activity.In both trials,C-7 showed greater inhibition than Itraconazole,the positive control.4.Abnormal activation of Hedgehog signal is related to proliferation and metastasis of human non-small cell lung cancer cells.Compound C-7 and C-14 were used to conduct cell apoptosis test,plate cloning assay,cell migration test,ROS test and mitochondrial membrane potential test on human non-small cell lung cancer cell A549.The results proved that C-7 and C-14 could inhibit the growth and migration of cell A549 by inhibiting Hedgehog signaling pathway.It has the potential to be used as a candidate drug for further preclinical bioactivity study.