Peer-Reviewed Journal Details
Mandatory Fields
Kruschel, Ryan D.; Buzid, Alyah; Khandavilli, Udaya B. Rao; Lawrence, Simon E.; Glennon, Jeremy D.; McCarthy, Florence O.
Organic & Biomolecular Chemistry
Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines
Optional Fields
Lead compounds Amino acids Cell culture Cells Tumors Anti-cancer agents Anticancer potentials Cancer cell lines Electrochemical studies Growth inhibition Natural products Pharmacophores Resistant cells
The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition 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 activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.
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