Design,Synthesis And Biological Evaluation Of 3,5-Disubstituted-2-Aminopyrazines As Aurora Kinase Inhibitors

Aurora kinases is a kind of important mitotic kinases,which can participate in the stages of mitosis process such as centrosome replication,bipolar spindle formation,chromosome rearrangement,chromosome checkpoint monitoring and so on.It was observed that the kinases have been over-expressed in a wide variety of tumor cells,so they have been considered to be one of the important targets of anti-tumor drugs research.It was reported that 2-aminopyrazines as protein kinase such as Nek2?Chk1?PI3K-?inhibitors has been widely applied,but it is not applied to the Aurora kinase inhibitor up to now.For the purpose of finding small molecule compounds targeting to Aruroa kinase,a series of 3,5-disubstituted-2-aminopyrazines were designed and synthesized,then all compounds were biologically evaluated from the following aspects including enzyme iinhibition,tumor cell proliferation inhibition,cell cycle arrest and molecular docking simulation.Compound 21b and 21c exhibited more potent cytotoxicity against tumor cell lines with IC₅₀ values of 0.9-14.8?M,at the same time they inhibited enzyme with IC₅₀ less than 5 n M.Furthermore,compound 21b and 21c Inhibited Aurora kinase expression and arrests the cell cycle process to intervene in the cell proliferation,which induced G2/M cell cycle arrest in Hela cells.In summary,a series of 3,5-disubstituted-2-aminopyrazines were designed and synthesized in this paper.This series of compounds has the value of further development as Aurora inhibitors for anticancer activity.