Bioactivity of Substituted Copper Pyrithione Complexes

Abstract

Over the last century, metal complexes have been popularised in therapeutic drug design. Copper complexes have been particularly interesting due to their high stability constants and unique redox chemistry. Simple copper salts, such as CuCl2 have little cytotoxicity, but ligands have been designed that lead to therapeutically activity copper complexes. The copper complex of pyrithione, a well-known ionophore, has recently been identified as a potent antibacterial and anticancer agent. Copper pyrithione has been shown to inactivate β-lactamase enzymes (such as NDM-1), a key enzyme in the mechanism of antibiotic resistance of multidrug-resistant bacteria. Antibiotic resistance being a great threat to human health around the world, copper pyrithione has potential in the development of new drug molecules. Key issues of this complex remain, including its low bacterial selectivity and poor aqueous solubility. This thesis focuses on structural modifications of the copper pyrithione complex with an aim to improve aqueous solubility, as well as optimise bioactivity as antibacterial and anticancer agents.
The synthesis and characterisation are described of series of novel copper pyrithione complexes with functional groups variation in the pyrithione ligand. Derivatives include electron donating and electron withdrawing groups, aromatic substituents, and polyethylene glycol (PEG) chains. These complexes are subjected to physiochemical property analysis. Binding constant (log K), lipophilicity (log P) and solubility of some selected complexes are determined, and structure-property correlations are established in some cases. PEG-substituted complexes are highly soluble in water and possess a good balance of solubility and lipophilicity.
All complexes are screened against various multidrug-resistant bacterial species and the majority show good activity against Gram-positive bacterial species. One complex, [Cu(5-Me-PT)2], shows good selectivity towards bacterial cells over healthy mammalian Vero cells, which augurs well for their use as novel antibiotics. Antibiotic synergy studies of copper pyrithione complexes alongside β-lactam antibiotics are performed, which shows that copper pyrithione complexes can act in combination with known antibiotics (meropenem and ertapenem) to overcome resistance in β-lactam resistant bacterial strains. Furthermore, cytotoxicity studies are performed with pancreatic carcinoma, bone osteosarcoma and healthy retinal epithelial cells, leading to structure-activity relationships to be proposed. Many novel complexes show high anticancer activity, with one complex [Cu(3-OMe-PT)2] showing particularly notable activity, with nanomolar inhibitory concentration (IC50 value) against pancreatic cancer.
In next part of this project, the synthesis and characterisation of a fluorescent tagged copper pyrithione derivative using an alkyne-azide ‘click’ reaction is described. Photoluminescence properties of this complex are determined utilising UV/Vis absorption and fluorescence spectroscopies. Copper conjugation quenches the fluorescence emission of the fluorescent tag to some extent. Fluorescence microscopy study reveals this complex can enter and be visible inside live cells, showing specific localisation around the endoplasmic reticulum.
Finally, some non-pyrithione copper complexes are described with an oxygen analogue of pyrithione showing particularly good bioactivity against both bacteria and cancer cells.