Two birds one stone: β-fluoropyrrolyl-cysteine S<sub>N</sub>Ar chemistry enabling functional porphyrin bioconjugation
Guoqing Jin, Jingxiang Wang, Jianhua Lü, Hang Zhang, Yuhang Yao, Yingying Ning, Hua Lu, Song Gao, Jun‐Long Zhang
Abstract
Ar chemistry, in which the β-fluorine of porphyrin is selectively replaced by a cysteine in either peptides or proteins to generate novel β-peptidyl/proteic porphyrins. Notably, due to the distinct electronic nature between fluorine and sulfur, such replacement makes the Q band red-shift to the near-infrared region (NIR, >700 nm). This facilitates intersystem crossing (ISC) to enhance the triplet population and thus singlet oxygen production. This new methodology features water tolerance, a fast reaction time (15 min), good chemo-selectivity, and broad substrate scope, including various peptides and proteins under mild conditions. To demonstrate its potential, we applied porphyrin β-bioconjugates in several scenarios, including (1) cytosolic delivery of functional proteins, (2) metabolic glycan labeling, (3) caspase-3 detection, and (4) tumor-targeting phototheranostics.