New reactions and substrates for orthogonal bioconjugation

The search for new and more efficient ligand-targeted drugs is always a challenge to overcome the side effects of therapeutic treatments. In these systems, a stimuli sensitive linker plays a crucial role for stability under physiological conditions and for selective release. Such structures are commonly used both for prodrug design and in more complex systems such as ADCs, where each component needs to be optimised for its therapeutic purpose and biological target. Several cleavable linkers can be found in the literature, but the main criticism of these molecules is the limited range of functional groups that can be bonded to them. Here we present the synthesis of novel self-immolative spacers that have demonstrated their generality in releasing of a wide range of functional groups using the NO2 group as a trigger. This group provides selectivity for the hypoxic environment and/or for the enzyme nitroreductase, which is over-expressed under hypoxic conditions such as in solid tumour cells and in bacterially infected tissues, and whose activity drives the reduction of aromatic nitro moieties. The developed systems have also been applied to construct ADCs. In addition, two novel photosensitive scaffolds for the development of photolabile protecting groups (PPGs) are discussed and investigated through computational chemistry.