The Design and Synthesis of Photoresponsive Molecules for the Sequential Modulation of Biomolecules

Spatiotemporal control over growth factor signalling is fundamental to tissue development and regeneration. While functionalised materials capable of enriching key biochemical signalling molecules have emerged as powerful tools for tissue engineering, existing strategies often lack the level of spatiotemporal precision required to mimic the complex, interdependent signalling cascades observed in vivo. This thesis addresses these limitations through the design and synthesis of photoresponsive molecules, alongside detailed photophysical and kinetic characterisation using small-molecule model systems, providing a chemical framework for the future development of photoresponsive biomaterials.
In this work, a range of photocages and photocleavable linkers based on coumarin and BODIPY scaffolds were produced. The syntheses of literature-reported molecules were investigated and optimised with scalability in mind, enabling access to gram-scale quantities of key intermediates and final compounds. In parallel, novel photoresponsive molecules were designed and synthesised, with emphasis placed on tuning absorption properties to generate a series of compounds with discrete absorption profiles suitable for wavelength-selective photoactivation.
Detailed photochemical kinetic studies were undertaken to quantitatively evaluate the decaging efficiency of the synthesised photoresponsive molecules across a range of visible wavelengths. Decaging was shown to proceed via first-order kinetics under all conditions examined, enabling direct and quantitative comparison of photorelease performance between compounds.
Preliminary peptide functionalisation studies were undertaken in which a lysine residue within a model peptide was selectively photocaged using an orthogonal deprotection workflow. Subsequent photochemical studies demonstrated that the installed photocage retained its photolytic activity upon irradiation at 365 nm. In parallel, a synthetic workflow for the photocaging of glutamic acid residues was also developed, but time constraints precluded full photochemical evaluation of this system.
The methodologies described in this thesis provide a foundation for the development of photoresponsive materials with dynamic control over biomolecular interactions and sequestration. Such systems have the potential to better resemble native cell growth environments by mimicking the complexity of biological signalling cascades, offering new opportunities for future control of stem cell fate and the advancement of tissue engineering strategies.