Designed Bond Cleavage Reactions for Next-Generation Therapeutics

Abstract

Creating ways for tissue-specific drug activation remains a significant challenge in modern medicine. Traditional approaches to drug delivery often lack precision, leading to unwanted side effects and reduced therapeutic efficacy. This PhD thesis explores two innovative approaches to overcome these challenges by developing novel prodrug systems that enable targeted activation in diseased tissues. The first project focuses on a metal-mediated amide bond-cleavage reaction from a pentenoic group by using Au salt (Na[AuCl4]) for prodrug activation in aqueous systems. Central to this strategy is a cyclisation step involving the formation of a 5-membered ring intermediate that undergoes rapid hydrolysis to release the free amine. The strategic introduction of a leaving group at the allyl position of the pentenoic group facilitated dual-release through π-acid catalysed substitution. The reaction allowed the traceless release of cytotoxic agents such as monomethyl auristatin E (MMAE) from antibody-drug conjugates (ADCs). The efficacy of this approach was also evaluated in a colorectal zebrafish xenograft model, offering promising insights into the application of Au complexes beyond those in catalysis to bond-cleavage reactions for cancer therapy. The second project aims to address the inherent challenges of covalent inhibitors (CIs), which pose risks of off-target effects despite being a significant proportion of small-molecule therapeutics. Chemical moieties, such as the ,-unsaturated system in acrylamides, make it challenging to design a prodrug approach. Here, we explore the use of caged cyanoacrylates, which are designed to remain inert until activated by a rapid C–C bond-cleaving decarboxylative elimination reaction. Further, we propose an in situ generation of reactive species for the protein of interest in disease cells. The prodrug can be selectively activated by caging the reactive Michael acceptor with a carboxylate group and equipping it with a leaving group at the -position, which could help reduce off-target effects and enhance safety. These projects contribute to advancing targeted therapies by selective activation of prodrugs and potentially covalent inhibitors. The findings could pave the way for safer, more effective treatments and have broader implications for future therapeutic designs.