Synthesis And Anticancer Activity Of Stable Nitroxyl Radicals Labeled 2,4-diaminopyrimidines 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.Recently,it was reported that a class of 2,4-diaminopyrimidines Aurora A inhibitors with excellent selectively for Aurora A over Aurora B.However,their antiproliferative activities were not high due to their low solubility and/or permeability.The stable nitroxides are effective transporter,and helping to 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,three series of stable nitroxides labeled pyrimidines were designed,synthesized,and evaluated for their biological activities including antiproliferation,inhibition against Aurora kinases and cell cycle effects.The study on the physical and chemical properties has shown that the introduction of nitroxides can improve the water-soluble of target compounds.These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control,especially compound TM 26,which showed the highest cytotoxicities,with ICso values of 1.0-8.0 ?M.Compound TM 26 had more than 67-fold more selectivity for Aurora A over Aurora B,and molecular docking analysis indicated that compound TM 26 form better interaction with Aurora A both from the perspective of structure and energy.Furthermore,compound TM 26 induced G2/M cell cycle arrest in HepG2 cells.This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.