Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties

Simon J. Allison (), Jaroslaw Bryk, Christopher J. Clemett, Robert A. Faulkner, Michael Ginger, Hollie B. S. Griffiths, Jane Harmer, P. Jane Owen-Lynch, Emma Pinder, Heiko Wurdak, Roger M. Phillips () and Craig R. Rice ()
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Simon J. Allison: University of Huddersfield Queensgate
Jaroslaw Bryk: University of Huddersfield Queensgate
Christopher J. Clemett: University of Huddersfield Queensgate
Robert A. Faulkner: University of Huddersfield Queensgate
Michael Ginger: University of Huddersfield Queensgate
Hollie B. S. Griffiths: University of Huddersfield Queensgate
Jane Harmer: University of Huddersfield Queensgate
P. Jane Owen-Lynch: University of Huddersfield Queensgate
Emma Pinder: University of Huddersfield Queensgate
Heiko Wurdak: University of Leeds
Roger M. Phillips: University of Huddersfield Queensgate
Craig R. Rice: University of Huddersfield Queensgate

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or ‘binders’ have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43ˉ, SO42ˉ or PhOPO32ˉ) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.

Date: 2021
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DOI: 10.1038/s41467-021-23983-3

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