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

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Abstract

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.

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

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Article information


Submitted
12 Nov 2019
Accepted
18 Dec 2019
First published
18 Dec 2019

Org. Biomol. Chem., 2020, Advance Article
Article type
Paper

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

R. D. Kruschel, A. Buzid, U. B. R. Khandavilli, S. E. Lawrence, J. D. Glennon and F. O. McCarthy, Org. Biomol. Chem., 2020, Advance Article , DOI: 10.1039/C9OB02441G

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