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  • br Introduction The process of mitosis is highly complex and


    Introduction The process of mitosis is highly complex and tightly regulated. This phase of the Biocytin resulted in two identical daughter cells. The aurora kinases (aurora A, B, and C) are a family of three highly homologous serine-threonine protein kinases that play a key role in regulating the mitosis process [1]. Since their discovery in Drosophila in 1995 [2], aurora kinases have received special attention both in the academic and in the pharmaceutical communities because people realized that defects in this kinases led to severe mitotic abnormality [3,4]. Aurora A and B showed great sequence similarity, especially within their kinase domains (71% identical) [5]. Aurora A accumulates at the G2/M phase of the mitosis, which has a vital role in centrosome maturation and separation, bipolar spindle assembly. Aurora B also accumulates during the lead-up to mitosis, with peak kinase activity occurring slightly later than aurora A. Aurora C has a similar function as aurora B and has a specific effect on male meiosis [3]. We have recently reported a series of N-trisubstituted (at C2, C4, and C6) pyrimidine derivatives as aurora kinase inhibitors based on the structure of VX-680 (Vertex, pan aurora A/B/C inhibitor) [6] and ENMD 2076 (EntreMed, aurora-A selective inhibitor) [7]. This work led to the discovery of several potent inhibitors, including compounds 1, 2, 3, which inhibit aurora A kinase with IC50 = 12, 46 and 22 nM [8]. We also demonstrated a simultaneous administration of compound 1 and epirubicin can synergistically inhibit the growth of human breast cancer cells [9]. Our early study on molecular docking revealed that the N and NH of the amino pyrazole form hydrogen bonds to Ala211 and Ala213 in the hinge region of aurora A with the N-methyl piperazine substituent pointing to the solvent accessible area. In addition, C2 substituent occupying a lipophilic pocket accommodates larger substituent. As a result, subtle modification on the N-substituted side chain at the C2 position of pyrimidine backbone greatly affects enzyme inhibitory and cellular activities (Fig. 1). Herein, we optimized the structures of lead compounds 2 and 3 by subtly adjusting the N-substituted side chain at the C2 position of pyrimidine. We identified that fluorinated compound 11j was the best aurora kinase inhibitor with highest anticancer potency and favorable stability.
    Results and discussion
    Conclusion We designed and synthesized twelve new N-trisubstituted pyrimidine derivatives, which are potent aurora kinase inhibitors. 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 visibly suppressed the growth of U937 xenograft tumors in vivo. 11j can induce 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.
    Conflicts of interest
    Introduction Aurora kinases are characterized as a novel subfamily of serine/threonine kinases and have been shown to play essential roles in the control of cell division in eukaryotes (Katayama et al., 2003, Fu et al., 2007, Goldenson and Crispino, 2015). What's more, the expression level and catalytic activity of Aurora kinases are highly elevated in many human cancers and can be used as a prognostic marker and therapeutic target (Fu et al., 2007, Kelly et al., 2011, Goldenson and Crispino, 2015). Aurora kinase was first discovered in the fruit fly, Drosophila melanogaster (Glover et al., 1995). To date, three members of Aurora kinases, namely Aurora A, B and C, have been identified (Nigg, 2001, Fu et al., 2007). All Aurora proteins share a high sequence similarity among eukaryotes (Goldenson and Crispino, 2015), and have a common catalytic domain of the serine/threonine kinase (S_TKc) that displays a protein kinase activity (Kimura et al., 1998). Moreover, the types of Aurora kinases vary in different organisms. For example, only one Aurora kinase exsits in the yeast, Saccharomyces cerevisiae (Chan and Botstein, 1993). The fruit fly and the nematode, Caenorhabditis elegans have two Aurora kinases, namely Aurora A and B (Fu et al., 2007). All three types of Aurora kinases can be found in mammals (Nigg, 2001).