Coumarin-Based Fluorescent Inhibitors for Photocontrollable Bioactivation

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-2nitrobenzyl 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 immuneresponsive macrophages. This provides a novel prodrug strategy of modulating druggable fluorophore backbones to achieve spatiotemporally controllable drug release for precise cancer treatment.

Recent progress of organic fluorescent molecules for bioimaging applications: cancer-relevant biomarkers

“…On the other hand, developing fluorescent and bio-activated small molecules is a potential strategy for cancer theranostics and research into novel drugs, which could monitor the enzyme activity level by fluorescence response and regulate the bio-activity of the cancer enzyme involved by the molecular activity mechanism. 109–114 Last but not least, the ultimate thrust of this research should be on clinical applications of these probes in imaging, diagnosis, and drug delivery systems based on the basic knowledge acquired from these studies.…”

Fluorogenic In Situ Thioacetalization: Expanding the Chemical Space of Fluorescent Probes, Including Unorthodox, Bifurcated, and Mechanosensitive Chalcogen Bonds

“…Thio/acetals are popular functional groups in fluorescent probes. Thioacetals have been used for mercury sensing, − quenching, − and the detection of reactive oxygen species, − while acetals have been used to sense pH changes, − detect metal ions, − visualize and modulate enzyme activity, − and for photochromic switching − and super-resolution microscopy . Usually, the conversion of aldehydes into thio/acetals is designed to turn off fluorescence, or vice versa , for different reasons.…”

Construction of Coumarin-Based Bioorthogonal Macromolecular Probes for Photoactivation

“…Fluorescence imaging techniques have been remarkably developed for the study of biological events over the past decades. − Modifications of biomolecules with photolabile fluorescent probes could provide a spatiotemporal fluorescence “off–on” mode upon photoactivation, − enabling the visualization of the localization and trafficking of biomolecules in living cells. − Coumarins are well known for bioimaging and biosensing because of their bright fluorescence and modifiable backbones. At the same time, coumarins also exist as potent chemical inhibitors in treating cancer. , We previously established a novel fluorescent inhibitor system , where photoactivatable coumarins integrated their fluorescence imaging characteristics with druggable backbones to achieve a stimulus-controllable drug release for cancer treatment. , However, it is still challenging for coumarin-based small-molecular probes to directly monitor single biomacromolecular species in cells because of the nonspecific localization resulting in unpredictable visualization.…”

“…At the same time, coumarins also exist as potent chemical inhibitors in treating cancer. 19,20 We previously established a novel fluorescent inhibitor system 21,22 where photoactivatable coumarins integrated their fluorescence imaging characteristics with druggable backbones to achieve a stimulus-controllable drug release for cancer treatment. 23,24 However, it is still challenging for coumarin-based smallmolecular probes to directly monitor single biomacromolecular species in cells because of the nonspecific localization resulting in unpredictable visualization.…”