Discovery of Potent Isoquinolinequinone -Oxides to Overcome Cancer Multidrug Resistance.

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ -oxide derivatives in two isomeric families, both exhibiting nanomolar GI against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.