[2.2.1]Heterobicyclic Bromovinyl Sulfones for Thiol-Triggered Strategies in Linker Chemistry: Aza- vs Oxa-Norbornadienic Systems

Azanorbornadienes (ANDs) containing a bromovinyl sulfone are able to accept a first thiol and, in a further stage, fragment upon reaction with a second thiol. This fragmentation has been studied in a collection of differently substituted ANDs. The substitution pattern of the AND influences the rate of the first thiolation and, specially, the further fragmentation. <i>N</i>-pyramidalization of selected ANDs was demonstrated via X-ray diffraction. This structural feature attenuates the resonance effect of N-substituents in the further reactivity of ANDs. A comparison with related oxanorbornadienes is also reported. The installation of a fluorogenic AND onto a single domain Antibody against PD-L1 (PD-L1 sdAb) resulted in a conjugate capable of releasing the corresponding fluorogenic pyrrole in the presence of glutathione (GSH) under physiological conditions. Overall, these scaffolds demonstrate potential to be implemented as new drug delivery systems.