Synthesis And Anticancer Activity Of 2,4-diaminopyrimidines And Phthalazin-1-ones As Aurora-a Kinase Inhibitors

Aurora kinases are a family of mitotic serine/threonine kinases,which have been implicated in several vital events in mitosis.Deregulation of Aurora kinase activity can result in mitotic abnormality and genetic instability,leading to defects in centrosome function,spindle assembly,chromosome alignment,and cytokinesis.So they have received significant attention as new targets for anticancer therapy.It was reported that antiproliferative activities of a class of 2,4-diaminopyrimidines Aurora-A inhibitors were not high due to their low solubility and/or permeability.The stable nitroxides can increase the solubility of drugs,prompting drug priority through the cancer cell membrane.In order to find effective antitumor drugs selectively targeted to Aruroa-A kinase,two series of stable nitroxides labeled or not pyrimidines and phthalazin-1-ones were designed,synthesized,and evaluated for their biological activities including antiproliferation,inhibition against Aurora kinases and cell cycle effects.These 2,4-diaminopyrimidines and phthalazin-1-ones compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680control,especially compound TZ 2,TZ 5 and TZ 10,which showed the highest cytotoxicities,with IC₅₀ values of 1μM.While,they have little inhibitory effect of Aurora-A and B.Furthermore,compound TZ 5 and TZ 10 induced S cell cycle arrest in A-549 cells.According to the cytotoxicity against tumor cell lines compared with the VX-680control,Only TZ 19 of these phthalazin-1-ones compounds exhibited more potent,which showed the highest cytotoxicities,with IC₅₀ values of 2.2μM.Compound TZ19 had more selectivity for Aurora-A over Aurora-B,Furthermore,compound TZ 19induced G2/M cell cycle arrest in He La cells.This series of compounds also has the potential for further development as selective Aurora-A inhibitors for anticancer activity.In summary,two types of compounds were designed and synthesized including pyrimidines and phthalazin-1-ones in this paper,compounds TZ 19 has a good cell activity on He La cells,pyrimidines compounds TZ 1～TZ 15 were on A-549 cells,but the target is unclear and need to have a further examination.