Synthesis and biological evaluation of aurora kinases inhibitors based on N-trisubstituted pyrimidine scaffold

Abstract

The inhibition of the members of aurora kinase family using ATP-competitive small molecules is an effective method for anticancer therapeutics. Based on our previous work, we synthesized 12 new N-trisubstituted pyrimidine derivatives and evaluated their biological activities and stabilities. Among them, compound 11j showed the best inhibition against aurora A kinase (IC₅₀ = 7.1 nM), human leukemia cell line U937 (IC₅₀ = 12.2 nM) and the growth of U937 xenograft tumors in vivo. By the flow cytometry and immunofluorescence analysis of U937, we found that compound 11j can induced polyploidy formation including (4N, 8N and 16N) and induce defects in both chromosome alignment and spindle formation. Furthermore, compound 11j exhibited good chemical, physical, and thermal stabilities. All these results suggested that 11j is a promising lead compound for further development of anticancer drugs.

Keywords: Anticancer drug; Aurora kinase inhibitor; Leukemia; N-trisubstituted pyrimidines; Synthesis.