On the Utilization of geminal-Dimethyl Hydroporphyrins and Tetraphenylethylenes in Photodynamic Therapy

Abstract

Chapter 1 introduces the main concepts of this thesis: photodynamic therapy (PDT), chlorins and photosensitizer arrays. In the case of PDT multiple topics are discussed, namely, the qualities of an ideal photosensitizer, the photochemical processes which facilitate cytotoxicity, different classes and generations of photosensitizers, and its applicability to cancer. Chlorins are introduced as the close relative to porphyrins they are. Initially, their spectroscopic differences are discussed. Following on from this, their natural origins, leading into their synthesis both from porphyrins and via de novo syntheses. The subject of chlorins in PDT is discussed, and why there is a need for a geminal-dimethyl hydroporphyrins. Lastly, the theory and prior utilization of photosensitizer arrays in PDT is discussed. Chapter 3 focuses on the synthesis of gem-dimethyl hydroporphyrins 3.36a and 3.36b, along with their photophysical analyses to determine their suitability as PSs in PDT. This chapter provides some of the basic science that is not currently present surrounding gem-dimethyl hydroporphyrins. Their photophysical properties were indicative of this class of compound being a suitable core for PS generation in PDT. Chapter 4 builds on the results presented in Chapter 3. Upon the knowledge that this core is suitable for PS generation, the system must be made more applicable to PDT through the implementation of bioconjugation handles, and more generally the implementation of motifs that aid the solubility of this class of compounds in aqueous media. Western half 4.72 was synthesized according to literature procedures, and throughout the sequence we present crystal structures of synthetic intermediates. Collection of multiple crystal structures along the synthetic pathway of organic compounds is something we believe to be good practice to assist data science investigations and offers potential insight into the electronic structure of intermediates. Further to this, we observed an unexpected diastereomeric resolution in 4.65, an uncharacterized yet known by-product in this synthesis. Eastern half 4.71 was designed with two orthogonal bioconjugation strategies, one novel and the other sparsely utilized. With the aim of solubilizing these systems in aqueous media, the synthesis of alkyne 4.69 was attempted. Unfortunately, its synthesis was unsuccessful. We sought to broaden our study and compare the synthesized chlorins to a series of analogous porphyrins. Photophysically all compounds presented typical spectra for their class; however, we were unable to determine a system for successfully determining the singlet oxygen quantum yield of all the desired species. In vitro evaluation of these five compounds exhibited stark contrasts regarding the solubility of these species, furthermore the lack of fluorescence of certain systems rendered multiple candidates non-suitable as PSs for PDT. Of the three most suitable candidates, two where chlorins. This work is the first example of geminal-dimethyl chlorins being utilized as PSs in PDT. Further to this it highlights the utility of sparsely substituted tetrapyrroles in PDT, however it further compounds the discussion of synthetic arduousity vs. photodynamic efficacy. Chapter 5 deals with a different strategy of enhancing the efficacy of PDT. Instead of enhancing the efficacy of a single PS, Chapter 5 surrounds the generation of novel PS arrays for PDT. The scaffold utilized was 1,1,2,2-tetraphenylethylene, given its myriad application and general utility through the phenomenon Aggregation Induced Emission (AIE). We utilized BODIPYs as our PS of choice, given their synthetic ease, and well-studied utility as PSs in PDT. Through varying the distance between the TPE and BODIPY cores differing responses were observed in every property analysed. We find that the addition of an ethynyl-linker enabled the retention of the AIE phenomenon and presented the subsequent array with more possible applications in the future. Regardless, both arrays synthesized were shown to suitably generate singlet oxygen, exhibiting their utility as PSs for PDT.