Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties
| Autor: | Emma Pinder, Christopher J. Clemett, Craig R. Rice, Jane Harmer, P. Jane Owen-Lynch, Roger M. Phillips, Hollie B. S. Griffiths, Robert A. Faulkner, Heiko Wurdak, Jarosław Bryk, Michael L. Ginger, Simon J. Allison |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Anions
0301 basic medicine Cancer therapy Cell Survival Stereochemistry Science Blotting Western Cryptand Supramolecular chemistry General Physics and Astronomy Antineoplastic Agents Crystallography X-Ray 010402 general chemistry 01 natural sciences Article General Biochemistry Genetics and Molecular Biology Cell Line Inhibitory Concentration 50 03 medical and health sciences Coordination Complexes Cell Line Tumor Neoplasms Autophagy Humans Receptor A549 cell Multidisciplinary Kinase Chemistry Phosphotransferases Self-assembly General Chemistry HCT116 Cells In vitro 0104 chemical sciences 030104 developmental biology A549 Cells Metals Cell culture Cancer cell HT29 Cells |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Artificial self-assembling systems such as anion receptors or ‘binders’ are largely unexplored for therapeutic applications. Here, the authors report self-assembling trimetallic cryptands containing copper, zinc or manganese that encapsulate a range of anions, are highly toxic to human cancer cell lines and show metal-dependent selectivity towards cancer vs. healthy cells linked to the selective inhibition of multiple kinases. |
| Databáze: | OpenAIRE |
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