Investigations into the chemopreventive potential of stilbenes, indolinones and isoindigos: Synthesis and mode of action studies

Abstract

The aim of this thesis was to test the hypothesis that structural modifcations of the stilbene resveratrol, a known chemopreventive agent, would result in compounds with greater phase II enzyme induction activity. To this end, two series were designed, synthesized and characterized. The first series comprised of 23 methoxystilbenes. The second series was based on the replacement of the phenolic ring B of resveratrol with a bioisosteric indolin-2-one moiety. Both libraries were evaluated for induction of NAD(P)H: quinone oxidoreductase 1 (NQO1) on the mouse hepatoma Hepa1c1c7 cells. Selected members were evaluated on a mutant cell line (c1) that lacked a functional CYP1A1 gene. They were also evaluated for induction of CYP1A1 activity on Hepa1c1c7 cells using the EROD assay. The antiproliferative activities of the compounds were investigated on human breast cancer cell (MCF7) and colon cancer (HCT116) cell lines, as well as a normal cell line (CCL186).