Peptide‐Carbazolyl Cyanobenzene Conjugates: Enabling Biomolecule Functionalization via Photoredox and Energy Transfer Catalysis

Since their discovery in 2012, carbazolyl (iso)phthalonitrile derivatives (Cz(I)PN) have found significant applications as photocatalysts in organic chemistry. Herein, we introduce two efficient methods for incorporating carbazolyl cyanobenzenes into various peptide sequences. The first method involves a photomediated decarboxylative functionalization of the C‐terminus of peptides, leading to the formation of various carbazolyl benzonitrile (CzBN) derivatives. The second method exploits a cysteine‐selective SNAr reaction on a fluorinated arene precursor, resulting in novel peptide‐3CzIPN (Triscarbazolyl‐isophthalonitrile) conjugates. Both types of conjugates maintain delayed fluorescence properties, exhibit similar or wider redox potential, and possess higher excited state energy when compared to currently used cyanoarenes. We demonstrated the photocatalytic activity of these conjugates first through a photo‐mediated peptide C‐terminal decarboxylative alkynylation. Then, water‐soluble peptide conjugates were used to catalyze a thiol‐ene reaction on cysteine in aqueous media. Finally, we achieved protein labeling via aryl azide excitation both in vitro and at the cellular level using peptide‐CzIPN conjugates. By incorporating a peptide ligand of the protein integrin αvβ3, proximity‐driven labeling next to this target was realized by aryl azide excitation in living cells, showing an excellent overlap with antibody‐based imaging. These findings reveal the potential of cyanoarene‐peptide conjugates for proximity‐driven photochemistry in a complex biological context.