Design, Syntheses and Characterization of Transition Metal Complexes for Utilization in Therapeutic Applications
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Design, Syntheses and Characterization of Transition Metal Complexes for Utilization in Therapeutic Applications

  • Author(s): Stenger-Smith, Jenny
  • Advisor(s): Mascharak, Pradip K
  • et al.

The use of metal complexes for therapeutic applications has been valuable in the treatment of diseases such as cancer and microbial infections. These metal complexes can be purposefully designed with ligands and metal centers that produce favorable properties for advancing the treatment of these diseases. In both microbial infections and cancer, resistance to commonly prescribed drugs is observed and new therapeutic methods with differing mechanisms of action is needed to further treat these diseases.Both gold and silver complexes have shown potent activity towards microbial infections. These metals are known to have multiple mechanism of actions which together produce the bactericidal activity. This is a particular advantage in the treatment of multi-drug resistant microbes and considering traditional organic based antibiotics typically have only one specific mechanism of action. In Chapter 2, silver complexes with benzothiazoles are evaluated for their antimicrobial activity using a skin and soft tissue infection (SSTI) model and proved to be potent bactericidal agents. The use of benzothiazoles as a ligand for silver is important in that they are members of a class of antibacterial agents and these ligands also exhibit fluorescence quenching when coordinated to the silver center. The interactions of the silver complexes with biological molecules (potentially leading to the bactericidal activity) is thus accompanied by the gradual turn on of fluorescence and provides a convenient means to track the release of Ag+. Chapter 3 utilizes gold complexes bearing triphenylphosphine for the treatment of bacterial and mycobacterial infections. Gold complexes with the same benzothiazoles used in Chapter 2 showed potent bactericidal activity with the SSTI model. Experiments indicated that the overall charge and structure of the gold complexes synthesized was important for the effectiveness of these species. Considering the results obtained from the antibacterial activity of the gold(I) triphenylphosphine ({Au(PPh3)}+) complexes, the second part of Chapter 3 focuses on the utility of this moiety towards mycobacterial infections. Mycobacterium are known to have very thick, hydrophobic and waxy outer membranes which are linked to their difficulty of treatment (Mycobacterium tuberculosis is responsible for Tuberculosis (TB) disease). Utilizing a complex with the {Au(PPh3)}+ unit and the clinically used TB drug pyrazinamide showed better antimicrobial activity compared to other gold species lacking this unit (likely brought about from the enhanced lipophilicity provided from the {Au(PPh3)}+ unit). The work described in Chapter 4 discusses light activated carbon monoxide (CO) releasing molecules (photoCORM) which have shown important therapeutic effects towards the eradication of cancer. The design strategy of extending the  conjugation of the ligand framework lead us to identify the first single photon excitation activation of manganese carbonyl photoCORMs with low power near IR light. While release of CO has been observed in this type of species with two photon excitations with near IR light, this two photon process requires expensive high power lasers. By using light in this region with low power as needed for single photon excitation, better penetration into tissues can be observed with less damage and allows for improved therapeutic effects. The transition metal complexes used in this work were designed to achieve specific results pertinent to the treatment of disease. The studies and experiments done with the complexes prove that these design principles are a useful tool to enhance the effectiveness of metal complexes for biological implementations.

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