Tetraarylethylene-based probes for biosensing applications

Moustafa Tarek Gabr

doi:10.17077/etd.005949

The identification of new and versatile molecular building blocks that can be utilized for construction of targeted bioactive compounds and biolabeling agents is an attractive strategy to advance fundamental studies of chemical biology. Tetraarylethylenes (TAEs) embody a particularly intriguing scaffold for this purpose because functionalized TAE derivatives are synthetically accessible in straightforward fashion and in many cases exhibit the phenomenon of aggregation-induced emission (AIE). This inherent property is characterized by the appearance of a fluorescence response when TAE molecules are placed in environments that impede free rotation about the aryl–ethylene bonds. While a few biosensors have been prepared that rely on the AIE effect in substituted tetraphenylethylene derivatives, the more general use of TAEs as central organizing motifs for fluorescent bioactive constructs has not been explored. Importantly, the modular assembly of targeted bioligands around a universal molecular platform imbued with one or more imaging modalities would greatly simplify detection and study of biomolecular constructs, and potentially aid in the diagnosis and treatment of numerous human diseases. This work is significant because synthetically streamlined modular approaches to novel multifunctional bioimaging agents are developed that can be easily adopted for use in a range of applications. The utility of TAEs as bioimaging platforms is expanded through incorporation of heteroaromatic fragments within the core TAE framework. The resulting tetra(hetero)arylethylenes are uniquely poised to facilitate construction of diverse targeted imaging and therapy agents, such as fluorescent cationic mitochondria-targeted TAEs that display mitochondria-specific accumulation in melanoma cells relative to normal human cells. Moreover, metal-coordinating TAEs are utilized to develop fluorescent sensors of biologically relevant and hazardous metal ions (Zn2+ and Hg2+). The sensors display selective metal ion-enhanced fluorescence in aqueous solution as a result of combining AIE activity of TAEs with metal chelating 1,1-bis(2-pyridylethylene) fragments. Another research direction discussed in this dissertation is development of phosphorescent metal complexes that exhibit AIE characteristics. The design strategy utilizes bis(2-pyridyl)ethylene or bis(2-quinolinyl)ethylene fragments incorporated into AIE active TAEs as bidentate ligands for rhenium. The synthetic flexibility of the TAE ligand platform enabled tuning of photophysical properties of these complexes. Moreover, incorporation of indole moiety into the TAE ligand afforded a new class of rhenium complexes that is recognized by indole binding proteins such as human serum albumin (HSA), which reveals potential applications of these complexes as probes of indole-binding proteins. This research was further extended to include development of rhenium complexes of benzothiazole-based TAEs as probes for monitoring aggregation of amyloid beta (Aβ) peptides which is crucial to advance our understanding of the molecular pathogenesis of Alzheimer’s disease (AD). Finally, TAEs were utilized to construct luminescent platinum(II) complexes for probing DNA mismatches and nuclease activity, therefore, these probes are promising candidates as early cancer diagnostic tools. The fundamental investigations performed in completing this dissertation will provide new molecular tools for additional basic and translational biomedical research in the future.

Tetraarylethylene-based probes for biosensing applications

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