Although several other activation methods of prodrugs have been designed and evaluated, photorelease shows immense potential due to its increased bioorthogonality and ease of control. Here, we present an in-depth study to improve prodrug photoreleasability and its biological implications. We began by examining the effect of aromatically substituted electron withdrawing and electron donating moieties on the photorelease kinetics of an ortho-nitrobenzyl carbonate group. In addition, we explored the impact of a benzylic deuterium substitution to determine if kinetic isotope effect (KIE) accounts for accelerated photorelease rates. However, a drawback of the o-nitrobenzyl group stems from the necessity of UV activation, which damages healthy tissue cells. To address this, we synthesized a biphenyl system in which we added aromatic conjugation to the nitrobenzene via a palladium-catalyzed cross-coupling in order to reduce required photon energy levels, thereby redshifting the photon trigger. The mechanistic insights derived from the initial photorelease assays were then applied towards the prodrugging of podophyllotoxin, a potent chemotherapeutic small molecule drug, in order to increase its pharmaceutical potential. Ultimately, the compatibility of such photoreleasable groups with targeted drug delivery systems was revealed through the development of a novel photoreleasable antibody-drug conjugate.

Optimizing the electronics of photoreleasable functional groups towards the design of next generation bioorthogonal prodrugging strategies

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.