Design, Synthesis And Anti-tumor Activity Of Novel Chiral PBK/TOPK Inhibitor

At present,malignant tumors have surpassed other diseases to become the"number one killer"of human life and health.Compared with traditional anti-tumor drugs,targeted anti-tumor drugs have become an important direction in the research of anti-tumor drugs.Molecular targeted therapy is a therapeutic method that specifically acts on tumor cells,which can mediate the signaling pathway of tumor cells,block the proliferation and metastasis of tumor cells,and induce apoptosis.In this study,PBK/TOPK was selected as the target,36 compounds were designed and synthesized,and their antitumor activities were preliminarily evaluated.According to related literatures,thiophene and[2,3-c]quinolones can effectively inhibit the activity of PBK/TOPK kinase.For example,OTS514 is a potent PBK/TOPK inhibitor.The subject of OTS514 as the lead compound,and the structure of drug molecules is replaced by the principle of bio-electronic isostatic and the principle of splicing.On the basis of structural design,six key intermediate was synthesized from 2-phenyl-1-propylamine,(R)-2-phenyl-1-propylamine,(S)-2-phenyl-1-propylam-ine,1-phenylethlamine,R-(+)-1-phenylethylamine,S-(-)-1-phenethylamine via acid-base neutralization,acylation,nitrification and reduction,then reaction with7-methoxy-6-acetoxy-4-chloro-quinazoline to synthesis of a series of aniline quinazoline derivatives.A design change 6-hydroxyl to modify thirty-six target compounds.The final production was characterized by ~1H NMR and LC-MS.The synthesis method is simple and feasible,and the raw materials are cheap and easy to obtain.We used MTT assay to study the antitumor activity of 20 target compounds in 36compounds synthesized by human lung cancer cell A549 and human breast cancer cell MDA-MB-231.The results showed that the activity of 3-dibutylamine propoxy at the 6-position of quinazoline was better than of 3-morpholinepropoxy,3-dimethylamine propoxy,3-tetrahydropyrrolidinyloxy and 3-hexahydropiperidine propoxy,the activity of amino acetylation on the side chain of the 4-position substituent benzene ring is greatly reduced,the activity of the R/S/racemic compound is equivalent.The activity of target compounds T-5,T-6,T-11,T-12,T-17,T-18,T-23,T-24,T-29,T-30,T-35 and T-36 were higher than that of the positive control Gefitinib in breast cancer cell MDA-MB-231.The target compounds T-6,T-11,T-12,T-18,T-24,T-29,T-30 and T-36 were more active than the positive control group in non-small cell lung cancer A549.The activity of target compounds T-6,T-12,T-24,T-30 and T-36 is comparable to that of OTS514,which is worthy of further study and provides a reference for further structural modification of PBK/TOPK inhibitors.