Glutathione-Responsive Fragmentation of Heteronorbornadiene-Based Thiovinyl Sulfones in Glioma Cells.

Abstract

We report the synthesis and fluorescent properties of dansylated heteronorbornadienes (HNDs) featuring a thiovinyl sulfone moiety as a thiol-reactive trigger. These systems undergo thiol addition which promotes fragmentation via a thioketal intermediate, leading to the release of fluorescent heterocycles (furan or pyrrole) and ketene S,S-acetals. Distinct fluorescence signatures enable real-time monitoring of the fragmentation process. We also report cellular studies to demonstrate that HND-thiovinyl sulfones are membrane-permeable and undergo glutathione (GSH)-mediated activation in glioma cells, resulting in intracellular release of fluorescent products. These findings establish HND-based architectures as promising platforms for the design of cleavable linkers in controlled release applications, particularly in targeted drug delivery and theranostics where stimuli-responsive behavior is essential.