Deuterium Editing of Small Molecules: A Case Study on Antitumor Activity of 1,4-Benzodiazepine-2,5-dione Derivatives.

Substituting hydrogen with deuterium in drug molecules is an appealing bioisosteric strategy for the generation of novel chemical entities in drug development. Optimizing lead compounds through deuteration has proven to be challenging and unpredictable, particularly for compounds with multiple metabolic sites. This study presents the pioneering achievement of substituting up to 19 hydrogen atoms with deuterium on 1,4-benzodiazepine-2,5-dione derivatives, shedding light on the structure-metabolism relationship and the impact of multiple deuterations on drug-like properties.

Bio-orthogonally Activatable Fluorescent Probe for Specific Imaging of Myeloid Cell Leukemia 1 Protein.

The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) has been increasingly identified as a promising potential therapeutic target attributed to its critical regulation effect in diverse cellar physiopathological events. Current fluorescence imaging strategies tend to be susceptible to the cellular microenvironment, and straightforward mapping of Mcl-1's level variation remains challenging. In this paper, an activatable "off-on" fluorescence strategy for Mcl-1 specific labeling was presented based on bio-orthogonal chemistry by introducing tetrazine-functionalized borondipyrromethene () as a fluorescent reporter and -cyclooctyne-derived indole-2-carboxylic acid () as an Mcl-1 targeting moiety.

Exploration of Thermally Activated Delayed Fluorescence (TADF)-Based Photoredox Catalyst To Establish the Mechanisms of Action for Photodynamic Therapy.

The mechanisms of action (MoA) have been proposed to further reduce the O dependence of photodynamic therapy (PDT) significantly. However, the triplet states of traditional photosensitizers are relatively short and also are easily deactivated by the quenching of HO or O. This is not conducive for the electron transfer in the photocatalytic process and poses a great obstacle to establish the MoA.

In Situ Fluorescence Imaging Reveals Contribution of Cerebral Hydroxyl Radicals in Hyperhomocysteinemia-Induced Alzheimer-like Dementia.

Elevated plasma level of homocysteine, also termed as hyperhomocysteinemia, is acknowledged as a significant and independent risk factor of Alzheimer's disease. However, the mechanistic insight has not been thoroughly elucidated yet. In this work, 3,5-dihydroxybenzyloxy was explored as the unique reaction trigger and integrated into the naphthalimide fluorophore via a carbamate linker to afford a new probe for OH imaging.

Endoplasmic Reticulum-Targeted Carbon Monoxide Photoreleaser for Drug-Induced Hepatotoxicity Remediation.

The alleviation of drug-induced liver injury has been a long-term public health concern. Growing evidence suggests that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of drug-induced hepatotoxicity. Therefore, the inhibition of ER stress has gradually become one of the important pathways to alleviate drug-induced liver injury.

Modified preparation of Si@C@TiO porous microspheres as anodes for high-performance lithium-ion batteries.

Microscale porous silicon materials have shown great application potential as anodes for next-generation lithium-ion batteries (LIBs); however, they face significant challenges, including mechanical structure instability, low intrinsic conductivity, and uncontrollable processing. In this study, a modified etching strategy combined with a facile sol-gel method is demonstrated to prepare microscale porous Si microspheres encapsulated by an inner amorphous carbon shell (≈10 nm) and an outer rigid anatase titanium oxide (TiO) shell (≈20 nm) (PSi@C@TiO), with the intact porous framework and core-shell-shell spherical structure. The interconnected pores can sufficiently accommodate the expansion of the Si core during lithiation.

Real-time visualization of the fluctuations in HOBr with AIE fluorescent probes during myocardial ischemia-reperfusion injury.

Two fluorescent probes (QM-S and QM-Se) featuring AIE properties were developed. The increased intracellular hypobromous acid (HOBr) in cardiomyocytes during MIRI was revealed with these probes. It was also observed that MIRI might be alleviated by combating oxidative stress, as well as inhibiting inflammation and ferroptosis, which could mediate oxidative stress.

Cyano-substituted stilbene (CSS)-based conjugated polymers: Photophysical properties exploration and applications in photodynamic therapy.

Conjugated polymers (CPs) have attracted great attention due to their excellent optical properties (such as large absorption cross section, signal amplification, high photostability etc.). As representative electron acceptors and organic small molecules which are easy to be synthesized and modified, cyano-substituted stilbene (CSS) derivatives are widely used to construct photoelectrical materials.

Identification of 1,4-Benzodiazepine-2,5-dione Derivatives as Potential Protein Synthesis Inhibitors with Highly Potent Anticancer Activity.

In this study, a random multiple human tumor cell line screening of an in-stock small-molecule chemical library was performed, and a hit compound, 1,4-benzodiazepine-2,5-dione (BZD, ; average 50% growth inhibitory concentration (GI = 0.24 μM)) to 60 tumor cell lines of nine types of human cancers, was identified. Subsequent structure-activity relationship (SAR) investigation disclosed a highly potent antitumor compound, , that was shown to exert promising effects against lung cancer cells by inducing cell cycle arrest and apoptosis.

Photocontrollable Fluorescence Imaging of Mitochondrial Peroxynitrite during Ferroptosis with High Fidelity.

Ferroptosis, a new regulatory cell death modality, underlies the pathogenesis of a broad range of disorders. Although much efforts have been made to uncover the molecular mechanisms, some mechanistic details of ferroptosis still remain poorly understood. Particularly, the functional relevance of mitochondrial reactive oxygen species (ROS) in ferroptosis is still highly controversial, which is partially due to the fact that it still remains puzzled how the mitochondrial ROS level varies during ferroptosis.

Two-photon fluorescence imaging of the cerebral peroxynitrite stress in Alzheimer's disease.

We designed and synthesized an oxindole-functionalized two-photon fluorescent probe based on a naphthalimide fluorophore, which enabled visualization of the overwhelming peroxynitrite flux during amyloid-β-induced neuronal ferroptosis and cerebral peroxynitrite stress in live mice with Alzheimer's disease.

Fabricating and Modulating Robust Multi-Photoaddressable Systems with the Derivatives of Diarylethylene and Donor-Acceptor Stenhouse Adducts.

Multi-photoaddressable systems (MPSs) belong to complex systems, which are comprised of more than one photoswitching molecule and can respond to different wavelengths of light simultaneously. While MPSs have been extensively applied in various fields, there are also some challenges, such as the deficiency of the wavelength-selective control and the interference from the poor thermodynamic stability of used photoswitching molecules. Herein, we reported two robust MPSs (MPS1/2) consisting of diarylethylene derivative (DAE) and different donor-acceptor Stenhouse adducts (DASAs), in which both opened and closed forms of DAE and opened forms of DASAs are thermodynamically stable.

Harnessing SeN to develop novel fluorescent probes for visualizing the variation of endogenous hypobromous acid (HOBr) during the administration of an immunotherapeutic agent.

By means of the formation of SeN, the ABT-Se and NDI-Se were developed to detect and visualize endogenous hypobromous acid (HOBr) in live cells. Specifically, the upregulation of HOBr was monitored by NDI-Se during the administration of an immunotherapeutic agent.

Dual-Channel Imaging of Amyloid-β Plaques and Peroxynitrite To Illuminate Their Correlations in Alzheimer's Disease Using a Unimolecular Two-Photon Fluorescent Probe.

Alzheimer's disease (AD) involves multiple pathological factors that mutually cooperate and closely contact to form interaction networks for jointly promoting the AD progression. Therefore, the comonitoring of different factors is particularly valuable for elucidating their level dynamics and complex interactions. However, such significant investigations remain a major challenge due to the lack of unimolecular fluorescent probes capable of simultaneous and discriminative visualization of multiple targets.

A light-activatable photosensitizer for photodynamic therapy based on a diarylethene derivative.

Herein, a light-activatable photosensitizer based on a diarylethene derivative, DAE-TPE, was developed for photodynamic therapy. Upon UV exposure, the "opened" form (OF) of DAE-TPE NPs was converted to the "closed" form (CF), and photosensitization was activated. The CF of DAE-TPE NPs exhibited sufficient photodynamic therapy effects upon HeLa cells.

A near-infrared fluorogenic probe for nuclear thiophenol detection.

Based on the thiolysis of dinitrophenyl ethers, a nucleus-targeted fluorescent probe, AQD, with bisalkylaminoanthraquinone as the fluorophore, was prepared for the near-infrared mapping of thiophenol in live cells, zebrafish, and mice.

Near-infrared photocontrolled therapeutic release via upconversion nanocomposites.

Photocontrolled therapeutic release holds great promise due to its versatile manipulability, superb spatiotemporal precision and minimal tissue invasiveness in biomedical purposes. However, most of light-responsive platforms thus far have relied on UV or visible light which substantially limit the potential applicability in living animals. In recent decades, near-infrared (NIR) light-mediated theranostic upconversion nanocomposites (UCNCs) that integrate conventional UV/Vis-sensitive materials and classic lanthanide-doped upconversion nanoparticles (UCNPs) have significantly promoted the development of deep-tissue photoreleasable therapeutics in vivo.

Visualizing peroxynitrite fluxes in myocardial cells using a new fluorescent probe reveals the protective effect of estrogen.

A tetraphenyl ethylene (TPE)-based fluorescent probe specific for ONOO- was developed to evaluate and verify the protective effect of estrogen on myocardial cells during OGD/R.

An HS-activated ratiometric CO photoreleaser enabled by excimer/monomer conversion.

Based on the excimer-monomer conversion of a pyrene-flavone hybrid, a ratiometric CO photoreleaser, PFN, was constructed for simultaneous H2S quantification and CO release in inflammatory cells.

A Facile, Versatile, and Highly Efficient Strategy for Peroxynitrite Bioimaging Enabled by Formamide Deformylation.

Peroxynitrite (ONOO) is attracting increasing attention due to its involvement in multiple facets of pathophysiological processes. However, ONOO bioimaging is still challenging due to (1) the lack of highly specific reaction triggers, (2) the tedious and low-yielding synthesis of current sophisticated probes, and (3) the lack of availability of a versatile chemical strategy. To address these challenges, on the basis of amine formylation/deformylation chemistry, we have developed a novel strategy for ONOO bioimaging.

Reactivity Modulation of Benzopyran-Coumarin Platform by Introducing Electron-Withdrawing Groups: Specific Detection of Biothiols and Peroxynitrite.

A variety of fluorophores have been designed and created to fabricate organic fluorescent probes. Among these fluorophores, benzopyran-coumarin (BC) based fluorescent platform has attracted increasing attention as it shows multiple appropriate fluorescent and imaging capacities. Nevertheless, the analytical potential of BC is still urgently needed to be further excavated as its detection performance is hindered by the inherent drawbacks of current BC skeleton, that is, limited number of reactive sites.

A two-photon fluorescent probe for ratiometric visualization of hypochlorous acid in live cells and animals based on a selenide oxidation/elimination tandem reaction.

Utilizing the oxidation/elimination tandem reaction of the α-phenylseleno carbonyl moiety, a two-photon fluorescent probe for ratiometric visualization of hypochlorous acid was developed. Its superior sensing performance and practical applications were well demonstrated.

Mitochondrial Peroxynitrite Mediation of Anthracycline-Induced Cardiotoxicity as Visualized by a Two-Photon Near-Infrared Fluorescent Probe.

Anthracyclines rank among the most efficacious anticancer medications. However, their clinical utility and oncologic efficacy are severely compromised by the cardiotoxicity risk facing the early-diagnosis difficulty and their unclear molecular mechanism. Herein, a two-photon-excitable and near-infrared-emissive fluorescent probe, TPNIR-FP, was fabricated and endowed with extraordinary specificity and sensitivity and a rapid response toward peroxynitrite (ONOO), as well as mitochondria-targeting ability.

A Two-Photon H O -Activated CO Photoreleaser.

Carbon monoxide (CO) is proposed as an active pharmaceutical agent with promising pharmaceutical prospects, as it has been involved in multifaceted modulation of diverse physiological and pathological processes. However, questions remain for therapeutic application of inhaled CO attributed to the inherent great affinity between CO and hemoglobin. Therefore, a robust platform with the function of CO transport and controllable release, depending on the local status of an organism, is of prominent significance for effectively avoiding the side effects of CO inhalation and optimizing the biological regulation function of CO.

Evaluating Drug-Induced Liver Injury and Its Remission via Discrimination and Imaging of HClO and HS with a Two-Photon Fluorescent Probe.

Drug-induced liver injury (DILI) has aroused wide concern. Finding new markers or indicators as well as detoxification molecules for DILI is of great significance and good application prospect, which can help develop effective preclinical screening methodology and corresponding treatment protocols. Herein, in this article, DILI caused by antidepressant drugs of duloxetine and fluoxetine and its remission were evaluated by a two-photon fluorescent probe, RPC-1, through discriminating and imaging HClO and HS simultaneously.