Pyrimidine is the important pharmacology core
Pyrimidine is the important pharmacology core in many Aurora inhibitors, such as VX-680, ENMD-2076, CYC-116 and ENMD-2076 . To identify additional effective Aurora inhibitors, we designed a series of 2,4-diaminopyrimidine compounds, our modeling studies suggested that the UK 356618 mg core as well as the secondary aromatic amine of the compounds form hydrogen bonds with the hinge region of the kinase domain and show selectively inhibition to Aurora A over Aurora B. Introduction of cyclopentyl amine on the C-4 in pyrimidine can adopt a binding mode similar to VX-680 . Furthermore, the differences of F, Cl, Br and NO2 at 5-C of pyrimidine was to investigate the effects of the electron-withdrawing on anti-proliferation and inhibition of Aurora kinase. Herein, we reported the synthesis, and evaluated their antiproliferation activities, inhibition of Aurora kinase and effects on the cell cycle.
Results and discussion
Conclusions Aurora kinases have been of interest as potential therapeutic targets in oncology. Here we describe a series of 2,4-diaminopyrimidine small molecule inhibitors that exert their cytotoxic activities in human tumor cell lines through inhibition of Aurora kinases. We specifically demonstrate that compound 11c was selective for inhibition of Aurora A over Aurora B in HeLa cells, and the molecular docking analysis revealed that 11c form better interaction with Aurora A than that with Aurora B. Treatment of HeLa cells with compound 11c also results in G2/M accumulation. These results suggest that these compounds have potential for further development in vivo as anticancer agents.
Acknowledgments This work was Financially supported by NSFC (21372110, 81372177), and the Fundamental Research Funds for the Central Universities, Lanzhou University (lzujbky-2014-k20).