The Development of a Novel Photolabile Protecting Group based on Xanthone Acetic Acid Photodecarboxylation for Corneal Drug Delivery

Abstract

This thesis describes the development of a new photolabile protecting group. It spans the detailed characterisation of the photochemical mechanism to the application of this group towards a novel drug delivery method. Photolabile protecting groups (PPGs) are essentially molecules (usually organic) that can be attached to another molecule of interest (often termed the 'effector') in a way that masks the activity of this second molecule. Upon excitation, the effector is released through a photochemical reaction allowing the rapid and controlled introduction of a high effector concentration. PPGs have been used in a wide variety of applications where either spatial or temporal control is desired. These include numerous dynamic biological studies, photolithography, and solid state synthesis to name a few. The photochemical mechanism that forms the basis of our new PPG is the photodecarboxylation of 2-xanthone acetic acid. Using a number of steady state and time resolved techniques, we have established that decarboxylation proceeds from the singlet excited state of 2- and 4-xanthone acetic acids (2-XAA and 4-XAA) yielding a short-lived carbanion intermediate. Interestingly, in a stark example of the ortho-meta effect, 3-xanthone acetic acid (3-XAA) is photostable. The carbanion generated from either 2- or 4-XAA is formed efficiently and is subsequently protonated very rapidly (tau < 20 ns) in aqueous solution. With proper substitution, this reactive carbanion can be harnessed to eliminate anionic leaving groups on the subnanosecond timescale. Both the release rate and efficiency of our PPGs represent a significant improvement over conventional PPGs. Additionally, the photochemistry of release is remarkably clean and the UVA absorption of the xanthone chromophore is quite high. For this reason, we have applied our new PPG to the development of a novel drug delivery method based on photorelease, a field that has not yet been greatly explored. More specifically, we have demonstrated the release of acyclovir, an antiviral commonly used for the treatment of ocular herpes simplex virus (HSV-1). We have also shown the ability of our PPG-acyclovir conjugate to suppress viral proliferation in corneal cells upon UVA irradiation.