Coumarin-Based Fluorescent Inhibitors for Photocontrollable Bioactivation
Fei Ren, Wendi Zhu, Shuke Yang, Chun Zhang, Yingchao Hou, Runqi Li, Jian Wen, Liang‐Hua Zou, Min Gao, Wenlong Wang, Zhihong Wu, Andong Shao
Abstract
Activation of the IRE-1/XBP-1 pathway is related to many human diseases. Coumarin-based derivatives acting as both IRE-1 inhibitors and bright fluorophores are highly desirable to establish an integrated fluorescent inhibitor system. Here, we take insights into the aqueous stability of a photocaged IRE-1 inhibitor PC-D-F07 through a structure activity relationship. The substituent effects indicate that the electron-withdrawing −NO 2 moiety in the photocage combined with the tricyclic coumarin fluorophore contribute to the structural stability of PC-D-F07. To optimize the photocage of PC-D-F07, we incorporate a 1-ethyl-2-nitrobenzyl or 2-nitrobenzyl photolabile moiety on the hydroxyl group of the IRE-1 inhibitor to generate RF-7 and RF-8 . Upon photoactivation, both RF-7 and RF-8 present an increased fluorescence response, sequentially enabling the unlocking of the ortho -1,3-dioxane acetal for the release of active IRE-1 inhibitors. Moreover, RF-7 exhibits a high repolarization ratio of converting M2-type tumor-associated macrophages (M2-TAMs) to M1-type immune-responsive macrophages. This provides a novel prodrug strategy of modulating druggable fluorophore backbones to achieve spatiotemporally controllable drug release for precise cancer treatment.