GROWTH INHIBITORY DIXONAPHTHOIMIDAZOLIUMS RELATED TO YM155: SYNTHESIS AND MECHANISTIC INVESTIGATIONS

Abstract

YM155 is a potent anticancer dioxonaphthoimidazolium and a survivin suppressor. However, its structure-activity relationship (SAR) is hitherto unreported and it has been associated with indiscriminate DNA damage. Here, a library of YM155 analogs was synthesized and tested on renal cell and non-small cell lung carcinoma lines to establish its SAR. AB1 (IC50 17 ? 44 nM) and AB7 (IC50 8.6 ? 29 nM) emerged as promising analogs. The dioxonaphthoimidazoliums were weak DNA intercalators and redox cyclers, with these properties bearing poor correlation to growth inhibition. The appearance of DNA damage marker ?H2AX was also concurrent with cleaved caspase 3 discounting DNA damage as a significant contributor towards YM155 activity. YM155 and AB1 inhibited p50 phosphorylation and disrupted the NF-?B pathway, possibly resulting in survivin downregulation. The library also showed potent activity as rogue stem cell clearing agents, with YM155, AB1 and AB7 inducing apoptosis and downregulating Sox2 in stem cells.