Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines
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Supplementary information
Date
2019-12-18
Authors
Kruschel, Ryan D.
Buzid, Alyah
Khandavilli, Udaya Bhaskara Rao
Lawrence, Simon E.
Glennon, Jeremy D.
McCarthy, Florence O.
Journal Title
Journal ISSN
Volume Title
Publisher
Royal Society of Chemistry
Published Version
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.
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Keywords
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
Citation
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
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https://pubs.rsc.org/en/content/articlelanding/2020/OB/C9OB02441G