New series of indazole based diarylureas derivatives were synthesized and their anticancer activity against H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901, MDA-MB-231 and PLC/PRF/5 were evaluated. In general, these derivatives showed superior or similar activity against most of these selected cancer cell lines with sorafenib as control. The effect of substituents on the indazole ring was investigated; the derivatives with trifluoromenthy or halogen substituent showed higher activity. Among them, Compound 1 , having 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties, exhibited the most potent anticancer activity; its efficacy and mechanisms were investigated comparing with sorafenib. Compound 1  significantly inhibited PLC/PRF/5 human hepatocellular carcinoma growth. Flow cytometry analysis indicated the induction of apoptosis and arrest of cell cycle in G1 phase. Western blotting showed the decrease of cyclin D1 and regulation of apoptotic proteins. Further analysis suggested that these effects of Compound 1  might arise from its roles in the inhibition of multi-kinases, including c-Kit and its downstream targets and the Wnt/�-catenin pathway in PLC/PRF/5 cells. In conclusion, Compound 1  could be developed as a potent anticancer agent that might supplant the use of sorafenib.

Synthesis of indazole based diarylurea derivatives and evaluation of their inhibition activity against human cancer cell growth

248th National Meeting (2014)

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