Applications for imidazophenanthridine-based heterocycles

Richmond, Craig J. (2009) Applications for imidazophenanthridine-based heterocycles. PhD thesis, University of Glasgow.

Abstract

The physical properties and reactivity of 2,3-dihydro-1H-imidazo[1,2-f]phenanthridinium cations (DIPs) and analogous heterocycles have been investigated. The adapted syntheses developed were applied to a range of aryl amines and more elaborate substrates, such as bifunctional aminoquinolinium cations and amino functionalised polyoxometalates (POMs).

1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridines (TIPs), an intermediate in the 3-step cascade synthesis of DIPs, have also been isolated. Derivatisation of the TIP structure at the imidazo-N position enables control of the reactivity of the intermediate with respect to electronic potential and pKa, allowing isolation of a selection of TIP structures. Correlations between these parameters and reaction outcome have been made and other influences such as steric and solvent effects have also been investigated.

Investigation of the structure and properties of the TIP framework led to the discovery of a pH dependent cyclisation between the ring-closed TIP form and the ring-open aminoethylphenanthridinium (AEP) form. The complementary TIP and AEP forms can be further manipulated by oxidation or reduction to convert them to their “pH-inert” forms, DIP and aminoethyldihydrophenanthridine (AEDP). These four interchangeable states formed the basis of a redox “lockable” molecular switch that could be useful for molecular level information processing and data storage.

The pH dependent cyclisation between the TIP and AEP forms was also investigated as a targeting mechanism for potential intercalating antitumour agents. The system looks to exploit the pH difference between cancerous tissues and normal tissue to combine high cytotoxicity with high selectivity, a desirable trait that is unfortunately absent in most chemotherapeutic agents. Preliminary in vitro assays have shown the TIP/AEP frameworks to have IC50 values in the pM range in human ovarian cancer cell lines, comparable to cisplatin and the closely related DIP intercalaters.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Heterocyclic chemistry, anticancer therapies, molecular devices
• Subjects: R Medicine > R Medicine (General); Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Cronin, Prof. Lee
• Date of Award: 2009
• Depositing User: Dr Craig Richmond
• Unique ID: glathesis:2009-1406
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 11 Jan 2010
• Last Modified: 04 Feb 2013 16:01
• URI: https://theses.gla.ac.uk/id/eprint/1406