Investigation into the viability of silver-N-heterocyclic carbenes as a class of chemotherapeutic agents

This thesis details the synthesis of various libraries of silver(I)-N-heterocyclic
carbenes (Ag(I)-NHCs) that are derived from natural and/or biologically relevant
non-toxic precursors. The complexes have been evaluated as potential classes
of chemotherapeutic agents. Furthermore, the use of polymers for
encapsulating the Ag(I)-NHC complexes was investigated for drug-delivery, and
a unique biological membrane has been used to examine the interaction of the
complexes with a membrane monolayer.
Ag(I)-NHC complexes derived from the xanthine precursors caffeine,
theophylline and theobromine were evaluated for anticancer activity against
eight cancerous cell lines, revealing IC50 values in the micromolar range.
Hydrophobicity measurements revealed that a fine balance of steric bulk around
the Ag-carbene bond and water solubility of the complex is required for the
antiproliferative activity. Complexes derived from the antifungal compound
clotrimazole were prepared. Various trends are discussed which relate
cytotoxicity to hydrophobicity, N-substitution on the carbene ligand,
counteranions, and substitution on the phenyl ring of clotrimazole. Selectivity
ratios for these complexes were calculated which revealed that complexes with
N-hydroxyethyl substituents on the ligand, which exhibit IC50 values similar to
those obtained for cisplatin, had excellent selectivity. Water-soluble complexes
bearing alcohol or carboxylic acid N-substituents on the ligand were prepared
from biologically relevant precursors. Hydrophobicity measurements and in vitro
cytotoxicity studies revealed similar hydrophobicity-cyctotoxicity trends to those
obtained for the clotrimazole-derived complexes. Overall, the results indicate
that intermediate lipophilicity is results in high antiproliferative activity.
Encapsulation of the Ag(I)-NHC complexes inside polymers via different routes
was investigated using non-toxic polyethylene glycol (PEG)-based polymers.
Dynamic light scattering (DLS) and scanning electron microscopy (SEM) studies
suggested successful encapsulation and/or coordination of the complexes with
the particles. In some cases, it was found that the cytotoxicity of the complexes
increased upon encapsulation with a polymer. Various Ag(I)-NHCs were
screened using a unique biological sensor that detects the interaction of the
complexes with a membrane monolayer. The results gave insight into the
possible mechanism of action of the complexes through their ability to interact
with biological membranes. Further development of this technique may provide
a valuable pre-screen for drug molecules, prior to more costly and time consuming
cell work.