Isoquinolinequinone <em>N</em>-oxides as anticancer agents effective against drug resistant cell lines

Abstract

The isoquinolinequinone (or isoquinoline-5,8-dione) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins with notable anticancer properties. Exploiting both families as seeds for drug discovery, we report for the first time on the structured development of an isoquinolinequinone N-oxide anticancer framework which exhibits growth inhibition of cancer cells in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows remarkable activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the isoquinolinequinone N-oxide framework and cytotoxicity. Preliminary studies were conducted to identify adduct binding to sulfur based biological nucleophiles glutathione and cysteine observed in vitro pointing to a potential mechanism of action. This new framework possesses significant anticancer potential and is the subject of intensive efforts to probe the effect on multidrug resistant cancer cells.