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

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.