Design, Synthesis, Cytotoxic Activity and Apoptosis-inducing Action of Novel Cinnoline Derivatives as Anticancer Agents

摘要

Aims: Tyrosine kinases and topoisomerase I are common target enzymes for the majority of the anticanceragents. In contrast to quinazolines and quinolines, kinase inhibitors and topoisomerase inhibitors incorporatingcinnoline scaffold are relatively infrequent. Thus the aim of this work was to replace the former scaffoldswith the latter one. Eighteen novel cinnoline derivatives were designed, synthesized and characterizedusing both microanalytical and spectral data.Methods: The cytotoxic activity of the new compounds was screened in vitro against both human breast cancercells and normal breast cells.Results: The enzymatic inhibition activity of promising candidates against both epidermal growth factor receptortyrosine kinase and topoisomerase I was accomplished.Conclusions: Cell cycle profiles were observed at IC50 doses of representative biologically active compounds.Compound 7 represented a new scaffold incorporating triazepinocinnoline ring system and showed outstandingcytotoxic activity against MCF-7 (0.049 μM), tyrosine kinase inhibition (0.22 μM), apoptosis percentage and thehighest selectivity index.