Thiol “Click” Chromene Ring Opening and Subsequent Cascade Nucleophilic Cyclization NIR Fluorescence Imaging Reveal High Levels of Thiol in Drug-Resistant Cells

Abstract

As the structural unit of natural products, chromene derivatives show a wide range of biological activity and pharmacological activity due to their unique photophysical and chemical properties. Ten years ago, our research group discovered the "thiol-chromene" click reaction, which achieved the selective detection of thiols through the change of the optical spectrum. Afterward, we attempted to develop various chromene-based fluorescent probes for imaging including near-infrared (NIR) probe, ratiometric probe, and multifunctional probe. However, how to integrate the fluorophore and reaction sites into the chromenebased skeleton remains challenging. In this work, we connected the chromene motif with the NIR fluorophore methylene blue utilizing a carbamate spacer to provide a new fluorescent probe (CM-NIR), which is triggered by thiols to open the pyran ring followed by attacking the carbamate by phenolate to releases the methylene blue. This novel cascade mechanism avoids the formation of paraquinone methides, which proved to be toxic to normal cells. CM-NIR also showed the specific imaging of thiols in living cells and mice. More importantly, the thiols level in drug-resistant cancer cells was found to be significantly higher than that in the corresponding cancer cell, which indicated that the thiols level may have an important role in cancer cells developing drug resistance.

Unique assembly of carbonylpyridinium and chromene reveals mitochondrial thiol starvation under ferroptosis and novel ferroptosis inducer

“…2d and S3). As we expected, the introduction of the carbonylpyridinium ion significantly improved the reaction rate compared with the probe (Cys: 7 min, Hcy: 3 min, GSH: 7 min) in our previous work [10] (Table S2). A significant increase in the fluorescence emission intensity at 575 nm was measured in DMSO/PBS (v/v, 1:9, pH 7.4) after the addition of Cys (0−3.6 equiv) into the mixture.…”

“…In our previous study, the chromene structure (8) was synthesized from the (2-hydroxy-5-methyl-1, 3phenylene)dimethanol in two steps. 10 To realize the condensation of compounds 8 and 9, a mild condition needs to be identified. When the catalytic amount of acetic acid and piperidine were added with toluene as the solvent, the reaction was quite messy, with only a small amount of product of 10 obtained (Scheme S1).…”

“…9 We recently took note of the thiol-chromene "click" nucleophilic reaction and developed a sensing probe for thiol with prominent selectivity, which enables us to monitor the thiol fluctuation in various physiological and pathological processes.(Fig. 1a and 1b) [10][11][12][13][14] Ferroptosis is a unique type of non-apoptotic-regulated cell death culminating with an overwhelming lipid peroxidation downstream of metabolic dysfunctions [15][16] and holds the promise to be a novel therapeutic approach. [17][18] Recent research indicated that cysteine deprivation could induce the ferroptosis of pancreatic ductal adenocarcinoma.…”

Deep NIR-I Emissive Iridium(III) Complex Bearing D-A Ligand: Synthesis, Photophysical Properties and DFT/TDDFT Calculation

“…For example, phthalocyanine [27][28][29] and boron dipyrromethene dyes [30][31][32] can easily exhibit NIR emissions between 800 and 1000 nm and have been well investigated for in vivo applications. Methylene blue [33][34][35] and indocyanine green [36][37][38][39], approved by the government, have been widely used in clinical applications. However, owing to Crystals 2021, 11, 1038 2 of 11 their high chemical reactivity, most of these organic dyes can easily oxidize into molecular fragments, resulting in the loss or blue shift of luminescence.…”

“…Crystals 2021, 11, x FOR PEER REVIEW 2 of 11 applications. Methylene blue [33][34][35] and indocyanine green [36][37][38][39], approved by the government, have been widely used in clinical applications. However, owing to their high chemical reactivity, most of these organic dyes can easily oxidize into molecular fragments, resulting in the loss or blue shift of luminescence.…”