Design And Synthesis Of Two PLK1 Inhibitors With Different Chemical Skeleton Structures

The Polo-like kinases（PLKs）,members of the serine/threonine family of kinases,play a variety of roles in G2/M phase transition and have been identified as key regulators of cell mitosis.PLKs are highly conserved from yeast to human and five Polo-like kinases,PLK1,PLK2（Snk）,PLK3（Fnk）,PLK4 and PLK5 have been identified.Among them,PLK1 has the best characterized.PLK1 is highly expressed in lung cancer,breast cancer,gastric cancer,ovarian cancer,prostate cancer and other entities and blood cancers.PLK1 was therefore considered an attractive target for treatment of proliferative diseases.Currently,small molecule PLK1 inhibitors are being evaluated in human clinical trials.Several PLK1 inhibitors have shown promising results in phase I or II clinical trials.It was found that pyrimidine dinitrogen compounds and tetrahydropteridine compounds have good physical and biological characteristics.In this study,two novel ATP competitive compounds were designed as potential inhibitors of PLK1 through the structure-based drug molecular design strategy,The aim is to obtain PLK1inhibitors with high selectivity and good inhibitory activity.This paper focuses on the research progress of Polo-like kinases and inhibitors and PLK1 and its inhibitors.The structure-activity relationships of different types of Polo-like kinase inhibitors were summarized.In the experimental part,we designed and synthesized pyrimidine diazaheterocyclic PLK1inhibitors.According to this structure,tetrahydropteridine PLK1 inhibitors were designed and synthesized.The new molecular structures in the synthesis of the two compounds were confirmed by¹HNMR,¹³CNMR and HRMS.The synthesis scheme used in this paper has mild reaction conditions and simple post-processing.With the characteristics of low cost and high yield。The synthesized PLK1 inhibitor has novel structure,high selectivity and good inhibitory activity which provides a new idea for the development and selection of anticancer drugs.