A Tetrazine‐Caged Carbon‐Dipyrromethene as a Bioorthogonally Activatable Fluorescent Probe

Abstract

A water‐soluble 1,2,4,5‐tetrazine‐substituted carbon‐dipyrromethene (C–DIPY) was synthesized from the previously reported carbonyl pyrrole dimer through a two‐step procedure. Owing to the presence of a tetrazine moiety, the fluorescence emission of this compound was largely quenched in phosphate‐buffered saline at pH 7.4. Upon addition of a bicyclo[6.1.0]non‐4‐yne (BCN) derivative, the tetrazine‐based quenching component of the compound was disrupted through the inverse electron‐demand Diels‐Alder reaction to restore the fluorescence in up to 6.6‐fold. This bioorthogonal activation was also demonstrated using U‐87 MG human glioblastoma cells, in which the fluorescence intensity of this C–DIPY could be enhanced by 8.7‐fold upon post‐incubation with the BCN derivative. The results showed that this tetrazine‐caged C–DIPY can serve as a bioorthogonally activatable fluorescent probe for bioimaging. The compound, however, was found to reside preferentially in the lysosomes instead of the mitochondria of the cells as predicted based on its cationic character, which could be attributed to its energy‐dependent endocytic cellular uptake pathway, for which lysosomes are the end station.

Strategic Construction of meso-Aryl-Substituted N,N-Carbonyl-Bridged Dipyrrinones as Small, Bright, and Tunable Fluorophores

“…Among them, boron dipyrromethene (BODIPY A , Figure a), which consists of a dipyrrolic fragment complexed with a boron center, has found applications in diverse areas such as fluorescence imaging, diagnostic and therapeutic reagents, and optoelectronic materials due to its ease of accessibility and derivatization, and tunable photophysical and chemical properties. − Consequently, considerable efforts have been devoted to developing new synthetic methods to expand the range of fascinating fluorescent dyes similar to the BODIPY π-systems . One intriguing but less explored strategy involves replacing BF 2 units with carbon as the bridging linker, resulting in a rigid 5.6.5 fused-ring system with excellent properties. − An elegant example of this is the successful synthesis of carbon-dipyrromethene ( B ) by Guo et al, which employed methylene to replace BF 2 units…”