Rational Design and Synthesis of Novel Firefly Luciferin Analogues for Bioluminescence

Firefly luciferin, also called D-luciferin, is the natural compound that bioluminesces in certain beetles and flies. This small molecule has been used for bioluminescence imaging (BLI), for example in preclinical cancer research. This thesis concerns the synthesis of novel D-luciferin analogues and the investigation of their bioluminescence and photophysical properties to explore the development of red shifted and brighter analogues. Chapter one presents the history and background of D-luciferin, and the synthesis of D-luciferin and its analogues. The second chapter presents basic photophysical principles. The third chapter discusses the synthesis of boron-chelated rigid luciferin analogues. The fourth chapter begins by discussing the concept of excited state intramolecular proton transfer (ESIPT) and then moves onto the design and synthesis of potential ESIPT type rigid luciferin based on the skeleton of infra-luciferin (iLH2). The fifth chapter starts with a brief introduction of BODIPY and then discusses the development of BODIPY luciferin via a convergent synthetic route. The sixth chapter gives the basic idea of intramolecular charge transfer (ICT) and then demonstrates the synthesis of an ICT enhanced 4’,6’-hydroxybenzothiazole luciferin. The seventh chapter begins with the design of novel V-shaped benzo[1,2-d:4,3-d']bis(thiazole) core structure according to our computational study and then describes the synthesis of V-shaped luciferin analogues via an SNAr reaction. The eighth chapter summarises the results and suggests some future work plans. The final chapter includes experimental procedures and characterisation data. The thesis is fully referenced to the primary literature