Hepatocellular carcinoma (HCC) is an aggressive and life-threatening disease which caused enormous number of deaths worldwide. Limited success of current treatments reveals an urgent need for a more effective therapeutics. Literature has highlighted Aurora kinases as potential targets because they frequently overexpress in HCC patients and the expression is associated with poor clinical outcome. Our aim is to develop novel small-molecule inhibitorsagainst Aurora kinases with the hope to ameliorate disease burden. On the basis of our previous work on multikinase inhibitors, scaffold hopping strategy led to discovery of new bioisostere of critical ureido linker. Resultant molecules had different activity spectrum to parent arylureidooxindoles. The IC50 against Aurora-B kinase was submicromolar to nanomolar range but showed inactive to other screened tyrosine kinases except Flt-3. Cellular activity was demonstrated by selected compounds in which they decreased phosphorylation level of histone H3 in Hep3B and Huh-7 cells. Herein, we report series of oxindole based compounds as novel Aurora-B kinase inhibitor that showed cross inhibition to Flt-3, and provide a new lead for anti-cancer drug development.

Design and synthesis of pyridone-oxindole derivatives as novel Aurora-B kinase inhibitor

246th National Meeting (2013)

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