Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines

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Supplementary information
Kruschel, Ryan D.
Buzid, Alyah
Khandavilli, Udaya Bhaskara Rao
Lawrence, Simon E.
Glennon, Jeremy D.
McCarthy, Florence O.
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Royal Society of Chemistry
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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.
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
Kruschel, R. D., Buzid, A., Khandavilli, U. B. R., Lawrence, S. E., Glennon, J. D. and McCarthy, F. O. (2020) 'Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines', Organic & Biomolecular Chemistry, 18(3), pp. 557-568. doi: 10.1039/C9OB02441G