AbstractAnions are an essential component of all life. In particular, the phosphate anion is used extensively in the agricultural industry to improve crop yield and ultimately feed the population. However, phosphate reserves are rapidly depleting and overuse causes eutrophication through phosphate runoff which remains a critical environmental issue. One solution to these problems is the sequestering of aqueous phosphate through the use of self-assembled supramolecular anion receptors. Supramolecular chemistry concerns itself with the interactions between discrete molecular species, and in particular, self-assembly is an attractive field to develop anion receptors as complex, selective, efficient, and tuneable anion binding compounds can be constructed from smaller pre-programmed subunits. The essential biological need for phosphates is due to their presence in numerous cellular regulatory processes and, as a consequence, the ability to reliably bind this anion in aqueous and physiological
media may have important implications in biological systems.
With these goals in mind, research continued on a previously synthesised ligand (L 1). After improving the synthesis of one of the precursors, co-ordination with zinc(II) and manganese(II) in the presence of sulfate and phosphate led to trinuclear species (i.e. [(L 1)2M3(EO4)]n+ where M = Zn2+ or Mn2+ and E = S (n = 4) or P (n = 3)) being obtained, but in the absence of a strongly-binding anion, a mononuclear complex was instead observed (i.e. [(L 1)M]2+ where M = Zn2+ or Mn2+). Complexes obtained using these two metals led to the observed hydrolysis of phosphate monoesters; conversely, the copper-based complex instead bound to these anions, leading to investigation of the activity of the complex when
reacted with various phosphorylated amino acids, and subsequently, the potential activity of all three complexes toward cancer cells in vitro. Upon investigation, all complexes demonstrated toxicity to a variety of cancer cell lines. Whilst the manganese-based complex showed only modest selectivity compared to non-cancerous cells, the copper- and zinc-based complexes not only showed unprecedented potency even at the sub-micromolar level they also demonstrated selectivity indices of up to approximately 2,000-fold, indicating some potential application for these complexes in chemotherapy.
To further the research into anion receptor self-assembly and investigate the effects of ligand alteration on capsule anion-extraction selectivity, three new ligands were designed and synthesised. These new ligands all contained the same pyridyl-thiazole N-donor binding domains and the amine group capable of interaction with anions but the spacer unit was varied; from the central triethylamine unit that L1 is constructed from to a tris(aminomethyl)ethane unit in L2 , to a triamino-cyclohexane unit in L3 , to a tris(aminoethyl)methane unit in L4 . Co-ordination of these ligands to various copper(II) salts led to the formation of trinuclear cages encapsulating anions in two of the three ligands in both the solid-state and in mass spectrometry studies. Whilst the final ligand showed colour changes indicative of capsule formation, no complexes were isolated in the solid-state, possibly due to the lack of flexibility of the spacer and a decrease in the host volume due to the shortened length of the spacer unit.
In an effort to improve the practicality of anion extraction, two other ligands were designed and synthesised which incorporated hydrophobic aliphatic ester chains in order to increase the solubility of the final complex in organic solvents. To investigate the ability of these complexes to sequester hydrophilic anions from aqueous media, biphasic extraction experiments were performed where anion containing water samples were treated using immiscible organic solutions containing each complex; ion chromatography measurements of the aqueous layers before and after treatment indicated that phosphates were preferentially extracted by one of these ligands, and that a mere twenty-percent excess of complex to phosphate was sufficient to remove ninety-four percent of total phosphate concentration.
In this work three main important facets in the design and reactivity of self-assembled anion-binding cryptand have been demonstrated: 1) the ability to bind and hydrolyse phosphate can have very important biological implications, 2) the spacer unit can be varied significantly and as long as they are sufficiently flexible then a large variety of bridging units can be employed and these have the same desirable anion binding properties and 3) modification of the ligand chain will allow the formation of complexes that abstract anions into organic solvents – which may be useful for the removal of pollutant anion on an industrial scale. These results indicate a very promising future for supramolecular chemistry, with potential applications in both the pharmaceutical and industrial sectors being realised from experiments using very small changes to an already existing ligand.
|Date of Award||2023|
|Supervisor||Craig Rice (Main Supervisor) & Gareth Parkes (Co-Supervisor)|