Light Controlled Bio-inspired Small Molecules

The work presented in this thesis examines the design, preparation and evaluation of light controlled biologically inspired small molecules. Incorporation of light sensitivity was achieved through the introduction of a photoresponsive diarylethene group, into a specific position within the molecular structure of a biologically relevant compound. The diarylethene class of photoresponsive molecules can absorb light of a specific wavelength, and subsequently undergo a reversible, light induced isomerization reaction, to generate a new structure with a unique set of chemical and physical properties. This photoisomerization process, also referred to as photoswitching, allows for reversible manipulation of the modified biomolecule’s properties, and consequently its ability to interact with a target using light. During this thesis, two examples utilizing the diarylethene framework are presented as a means to control the properties; either geometric (steric) or electronic, of photoresponsive small molecules using light energy. In the first example, featured in Chapter 2, light is used to alter the binding affinity (and thus inhibitory potency) of a photoswitchable enzyme inhibitor. The design relies on the structural and geometrical changes that accompany photoswitching of the central diarylethene to achieve this. A series of inhibitor candidates, based on the bisindolylmaleimide class of protein kinase inhibitors, were synthesized and investigated. A number of challenges were encountered during the design process, including the poor photochemical performance and limited aqueous stability of the inhibitor candidates. Although, during the course of the project, two light controlled inhibitors with differing inhibition mechanisms were discovered. One derivative exhibited good in vitro inhibition, and its inhibitory activity could be switched from an inactive, “off” state, to an active, “on” state, with brief exposure to non-damaging visible light. A second derivative, self-assembled into large aggregate particles and interestingly, exhibited light dependent (more specifically, structure dependent) solubility in aqueous media. The aggregates were found to inhibit enzyme function in vitro, although through a non-specific adsorption mechanism. The aggregate assembly could be disrupted with exposure to visible light, which generated the water soluble isomer, and restored enzyme activity. In the second example, featured in Chapter 3, light is used to control the electronic properties of a photoisomerizable Pyridoxal 5’-phosphate (PLP) mimic and influence the rate of a racemization reaction. The design combines the essential structural features of PLP, which are an aldehyde and a pyridinium, with a diarylethene photoswitch. The inherent changes that take place to the structure of the diarylethene with photoisomerization, effectively allowed for reversible modulation of the degree of electronic connection between the aldehyde and pyridinium. Consequently, control over the cofactor mimic’s reactivity towards substrate was possible. In the inactive state, communication between the pyridinium and aldehyde are minimal, and as a result, the ability to convert a substrate to product is poor. Whereas in the active state, the extended communication pathway formed between the pyridinium and aldehyde, lead to a more efficient catalyst for substrate conversion.