Towards Photoredox-Cleavable Prodrugs

Abstract

Photouncaging is a field of study in which light is used to release or activate molecules from inactive precursors, e.g. prodrugs. Photouncaging is most often achieved through a direct release approach employing a chromophore as the photocaging group, which absorbs light and followingly undergoes cleavage. While this approach operationally simple, it requires complex photocaging groups, which have the inherent drawback of being unstable towards light. Photouncaging can also be achieved by a less-explored sensitised approach in which the photocaging group itself is inert to light and uncaging is mediated by a photosensitiser, which engages the photocaging group in energy transfer or redox reactions. The sensitised photouncaging approach overcomes the challenges encountered in direct photouncaging by employing simple light-stable photocaging groups. With the increasing popularity of visible-light photoredox chemistry in organic synthesis, there is an increasing number of photosensitiser-mediated reactions being reported, which can also be applied to photouncaging. For this project it was envisaged that a photooxidative approach would be useful for release of prodrugs carrying electron-rich benzyl groups as a photocage, which would be oxidised by a photocatalyst with molecular oxygen as a terminal oxidant. It was found that only sufficiently electron-rich benzyl groups underwent efficient photooxidative cleavage, and in particular the 2,4-dimethoxybenzyl group was identified as a suitable photocaging group. With the identified 2,4-dimethoxybenzyl photocaging group it was found that 2,4-dimethoxybenzylcarbamates, ethers and sulfonamides all underwent photooxidative cleavage, and release could be achieved by use of transitionmetal and organic photocatalysts, including riboflavin. The rate of release was found to be dependent on concentration, and the cleavage proceeded in minutes under high dilution. Attempts at extending the photooxidative cleavage to a proof-of-concept for prodrugs met with mixed results. While rapid prodrug release could be observed when releasing at μM concentrations, an in vitro proof-of-concept for this methodology was not achieved. In some cases, drug stability was too low under the cleavage conditions, while in other cases prodrug stability was not sufficiently high. Overall, this study represents a useful addition of knowledge to the fields of photoredox-mediated photouncaging and photocleavable prodrugs, though further work will be necessary to prove its applicability in prodrugs.