Since the discovery of the first stable silver N-heterocyclic carbene complex by Arduengo in 1991, the field of silver N-heterocyclic carbene complexes has expanded greatly. These complexes have been studied extensively for use in catalysis, as transmetallation agents, and more recently for pharmaceutical applications. Silver has been used for centuries as an anti-microbial agent, and more recently has been shown to have anti-tumor activity as well. Combination with the easily modified N-heterocyclic carbene ligand yields a drug that can be rationally designed for increased water solubility, increased lipophilicity, or to increase activity. These complexes have shown great results, and will be the main focus of this dissertation.
Chapter 1 of this dissertation reviews silver N-heterocyclic carbene complexes as promising antimicrobial agents and the evolution of the field over the past two decades. Chapter 2 discusses the synthesis of a new N-heterocyclic carbene backbone, 4,5,6,7-tetrachlorobenzimidazole, and the corresponding silver complexes for antimicrobial use. These complexes were then examined in vitro against a panel of clinical bacteria, displaying inhibitory concentrations between 0.25-4 µg/mL. Additionally, two of the silver complexes displayed antimicrobial activity against a silver-resistant E. coli strain.
Chapter 3 discusses the rational design of several new naphthalene containing imidazolium cations, the precursors to silver N-heterocyclic carbene complexes, for the use as anti-tumor drugs. These new imidazolium cations have been designed to increase water solubility, anti-tumor activity, and encapsulation efficiency into biodegradable delivery devices through modification of the substituents. These cations have demonstrated in vitro anti-tumor activity comparable to cisplatin against three types of lung cancer. The anti-tumor activity increased with the increase in the length of the alkyl chain substituent. Additionally, it was noted that the position of the alkyl chain on the naphthalene rings did not affect the anti-tumor activity of the cations.
Chapter 4 discusses the in vitro anti-tumor activity of silver carbene complexes based on selected imidazolium cations from chapter 3. These complexes have demonstrated an increase in water solubility in comparison to previously reported silver N-heterocyclic carbene anti-tumor complexes. Additionally, the complexes have displayed anti-tumor activity at clinically relevant levels, demonstrating IC50 values ranging from 5-25 µg/mL. In general, the anti-tumor activity increased as the length of the alkyl chain on the ligand increased. The highest activity was displayed by SCC44, which unlike the other complexes contained two naphthalene rings.