Search

Over the past decade, remarkable advances have been witnessed in the development of small-molecule probes. These molecular tools have been widely applied for interrogating proteins, pathways and drug–target interactions in preclinical research. While novel structures and designs are commonly explored in probe development, the clinical translation of small-molecule probes remains limited, primarily due to safety and regulatory considerations. Recent synergistic developments – interfacing novel chemical probes with complementary analytical technologies – have introduced and expedited diverse biomedical opportunities to molecularly characterize targeted drug interactions directly in the human body or through accessible clinical specimens (e.g., blood and ascites fluid). These integrated developments thus offer unprecedented opportunities for drug development, disease diagnostics and treatment monitoring. In this review, we discuss recent advances in the structure and design of small-molecule probes with novel functionalities and the integrated development with imaging, proteomics and other emerging technologies. We further highlight recent applications of integrated small-molecule technologies for the molecular analysis of drug–target interactions, including translational applications and emerging opportunities for whole-body imaging, tissue-based measurement and blood-based analysis. [ABSTRACT FROM AUTHOR]

Dual‐state emission luminogens (DSEgens) are receiving research interest in the construction of multifunctional materials due to their inherent advantage of high emission efficiency in both the molecularly dispersed solution state and the solid state. However, it remains challenging in synthesizing DSEgens via a delicate manipulation of the molecular structures. This work presents an example of bright DSEgen synthesis by tuning the molecular electronic structures and conformations. Three coumarin‐tetraphenylethylene (TPE) molecules with a donor‐acceptor electronic structure and highly twisting conformations have been synthesized. While compound resulting from direct conjugation of coumarin with a TPE unit shows aggregation‐induced emission, compound with an N,N‐diaminoethyl modification on the 7‐position of coumarin and compound with a further phenyl linker between coumarin and TPE units feature strong dual‐state emission. Benefiting from their strong solid emission and twisting conformations, these fluorophores display reversible mechanofluorochromism. Finally, applications for rewritable information storage in the solid state and live‐cell imaging in the solution state were demonstrated. [ABSTRACT FROM AUTHOR]

Shape‐morphing hydrogels bear promising prospects as soft actuators and for robotics. However, they are mostly restricted to applications in the abiotic domain due to the harsh physicochemical conditions typically necessary to induce shape morphing. Here, multilayer hydrogel actuator systems are developed using biocompatible and photocrosslinkable oxidized, methacrylated alginate and methacrylated gelatin that permit encapsulation and maintenance of living cells within the hydrogel actuators and implement programmed and controlled actuations with multiple shape changes. The hydrogel actuators encapsulating cells enable defined self‐folding and/or user‐regulated, on‐demand‐folding into specific 3D architectures under physiological conditions, with the capability to partially bioemulate complex developmental processes such as branching morphogenesis. The hydrogel actuator systems can be utilized as novel platforms for investigating the effect of programmed multiple‐step and reversible shape morphing on cellular behaviors in 3D extracellular matrix and the role of recapitulating developmental and healing morphogenic processes on promoting new complex tissue formation. [ABSTRACT FROM AUTHOR]

A novel Schiff base derivative (Z)-3-(4-(hexyloxy)phenyl)-2-(4-((E)-2-hydroxybenzylidene amino)phenyl)acrylonitrile ( L) was designed, synthesized and characterized. L was used as a Zn selective, turn-on, fluorescent chemosensor with a detection limit of 0.1 μM in DMF. 1:1 stoichiometric complex formation of L wih Zn was confirmed through fluorescent titration experiments and Job's plot. The enhancement of fluorescence intensity of L with addition of Zn is the consequence of the inhibited isomerization of the C=N bond, namely chelation-enhanced fluorescence (CHEF) effect. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Amine-functionalized a-cyanostilbene derivatives (Z)-2-(4-aminophenyl)-3-(4-butoxyphenyl)acrylonitrile (ABA) and (Z)-3-(4-butoxyphenyl)-2-[4-(butylamino)phenyl]acrylonitrile (BBA) were designed for specific recognition of picric acid (PA), an environmental and biological pollutant. The 1:1 host-guest complexes formed between the chemosensors and PA enhanced fluorescence quenching, thus leading to sensitive and selective detection in aqueous media and the solid phase. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) dysfunction is closely associated with a multitude of diseases, including nonalcoholic fatty liver disease (NAFLD). Therefore, it is imperative to develop fluorescent probes that specifically target LDs for the early detection and diagnosis of NAFLD. In this study, a series of lipophilic fluorophores CZ1-CZ4 that feature a D-π-A configuration were designed and synthesized based on the carbazole and tricocyanofuran derivatives. The photophysical data revealed that all four probes exhibited large Stokes shifts (~ 120 nm) in high-polarity solvents (e.g., DMSO) and demonstrated enhanced fluorescence in solvents ranging from low-polarity (e.g., 1,4-Dioxane) to high-polarity. Notably, by utilizing probe CZ1, we could specifically visualize LDs and captured high-quality images, even eliminating the need for a time-consuming wash procedure. Moreover, CZ1 enabled monitoring of LDs dynamic changes in-real time within live cells, and importantly, it could be used to effectively distinguish normal and NAFLD tissues at both the organ and in vivo level. This exceptional property of probe CZ1 provides a practical tool for the diagnosis and intervention of NAFLD. [ABSTRACT FROM AUTHOR]

Fluorophores are considered powerful tools for not only enabling the visualization of cell structures, substructures, and biological processes, but also making for the quantitative and qualitative measurement of various analytes in living systems. However, most fluorophores do not meet the diverse requirements for biological applications in terms of their photophysical and biological properties. Hybridization is an important strategy in molecular engineering that provides fluorophores with complementarity and multifunctionality. This review summarizes the basic strategies of hybridization with four classes of fluorophores, including xanthene, cyanine, coumarin, and BODIPY with a focus on their structure‐property relationship (SPR) and biological applications. This review aims to provide rational hybrid ideas for expanding the reservoir of knowledge regarding fluorophores and promoting the development of newly produced fluorophores for applications in the field of life sciences. [ABSTRACT FROM AUTHOR]

Abnormal expression of monoamine oxidase A (MAO−A) has been implicated in the development of human glioma, making MAO−A a promising target for therapy. Therefore, a rapid determination of MAO−A is critical for diagnosis. Through in silico screening of two‐photon fluorophores, we discovered that a derivative of N,N‐dimethyl‐naphthalenamine (pre‐mito) can effectively fit into the entrance of the MAO−A cavity. Substitutions on the N‐pyridine not only further explore the MAO−A cavity, but also enable mitochondrial targeting ability. The aminopropyl substituted molecule, CD1, showed the fastest MAO−A detection (within 20 s), high MAO−A affinity and selectivity. It was also used for in situ imaging of MAO−A in living cells, enabling a comparison of the MAO−A content in human glioma and paracancerous tissues. Our results demonstrate that optimizing the affinity binding‐based fluorogenic probes significantly improves their detection rate, providing a general approach for rapid detection probe design and optimization. [ABSTRACT FROM AUTHOR]

Abnormal expression of monoamine oxidase A (MAO−A) has been implicated in the development of human glioma, making MAO−A a promising target for therapy. Therefore, a rapid determination of MAO−A is critical for diagnosis. Through in silico screening of two‐photon fluorophores, we discovered that a derivative of N,N‐dimethyl‐naphthalenamine (pre‐mito) can effectively fit into the entrance of the MAO−A cavity. Substitutions on the N‐pyridine not only further explore the MAO−A cavity, but also enable mitochondrial targeting ability. The aminopropyl substituted molecule, CD1, showed the fastest MAO−A detection (within 20 s), high MAO−A affinity and selectivity. It was also used for in situ imaging of MAO−A in living cells, enabling a comparison of the MAO−A content in human glioma and paracancerous tissues. Our results demonstrate that optimizing the affinity binding‐based fluorogenic probes significantly improves their detection rate, providing a general approach for rapid detection probe design and optimization. [ABSTRACT FROM AUTHOR]

Lipid droplet (LD) dysfunction can result in various diseases, such as nonalcoholic fatty liver disease. Imaging agents built on dual‐state emission (DSE) molecules that fluoresce in both dilute solutions and the aggregated state are receiving attention as this type of probe could provide bright fluorescence signals at variable concentrations, avoiding false signal readout caused by the concentration fluctuation in living systems. Herein, we identified a red emissive molecule featuring DSE, from three newly synthesized molecules, for specific detection of LDs in live cells. The bioimaging abilities have been well confirmed by optical spectroscopies, theoretical calculations, cell experiments, as well as animal studies. The DSE probe is effective for LD detection at concentrations ranging from 1 μM to 100 μM while retaining high brightness and signal fidelity. This study provides a knowledge base for the future design of DSE‐active fluorescent probes for understanding LD‐related diseases. [ABSTRACT FROM AUTHOR]

Dual‐state emissive (DSE) materials with efficient emission both in solution and in the solid state can be used in complex environments. In this work, we demonstrate the synthesis of DSE materials by finely tuning the electronic structures of luminogens. Four carbazole‐cyanostyrene compounds with different terminal groups, i. e. CZ‐Ph‐H without additional substituent, CZ‐Ph‐TA with an N,N‐dimethylamino functional group, CZ‐Ph‐CN with a cyano group, and CZ‐Ph‐TB with a t‐butyl group, have been synthesized and their photophysical properties are fully investigated by spectroscopic studies, theoretical calculations, and crystallographic analysis. Interestingly, while CZ‐Ph‐H, CZ‐Ph‐CN, and CZ‐Ph‐TB are aggregation‐induced emissive (AIE) molecules only showing strong emission in the aggregated states (aggregate suspension and solid powder), CZ‐Ph‐TA is a DSE molecule showing strong emission in both dilute solution and aggregated states. In addition, CZ‐Ph‐TA could serve as a fluorescent probe for trace water analysis in organic solvents and picric acid (PA) detection in both dilute solution and aggregate suspension. CZ‐Ph‐TA also exhibits reversible mechanofluorochromism with a spectral shift of 21 nm. The synthesis of the N,N‐dimethylamino‐substituted molecule with excellent photophysical properties represents an important attempt to achieve DSE by finely tuning the electronic structures of molecules. [ABSTRACT FROM AUTHOR]

[Display omitted] • All four probes exhibited high sensitivity and specificity for polarity changes. • Probes CNL2 and CNL4 exhibited a long emission wavelength (>650 nm). • CNL2 and CNL4 possess excellent wash-free imaging capabilities and superior LDs targeting abilities. • CNL4 effectively monitors changes in LDs polarity under conditions of ferroptosis and oxidative stress. • CNL4 can be capable of monitoring the process of lipophagy and the early diagnosis of fatty liver at the tissue level. Lipid droplets (LDs), as primary cellular energy storage organelles, play essential roles not only in energy conservation but also in inflammatory responses, apoptosis, and the progression of diseases such as non-alcoholic fatty liver disease (NAFLD). Studies indicate that alterations in the polarity of LDs are closely linked to pathological factors like oxidative stress, ferroptosis, and lipophagy. Therefore, developing biological probes for precisely monitoring LDs polarity is crucial for understanding these biological phenomena and devising new therapeutic strategies. In this context, we synthesized four fluorescent probes (CNL1 - CNL4) to precisely monitor the polarity of LDs using triphenylamine and carbazole derivatives as electron donors and isophorone and benzopyranonitrile units as electron acceptors, employing intramolecular charge transfer (ICT) mechanism. Our findings demonstrated that all four probes exhibited high sensitivity and specificity for polarity changes. Probes CNL2 and CNL4 were sensitive to polarity, and their maximum fluorescence intensity and maximum emission wavelength demonstrated a good linear relationship with polarity parameters within a certain range. Biological experiments demonstrated that both CNL2 and CNL4 possess excellent wash-free imaging capabilities and superior LDs targeting abilities but also enable dynamic monitoring of LDs and respond well to changes in LDs polarity under varying concentrations of oleic acid stimulation. Due to its longer emission wavelength (>650 nm), boasting excellent photostability, and featuring a larger Stokes shift (≈168 nm in acetonitrile), probe CNL4 was selected for further studies. Furthermore, probe CNL4 effectively monitors changes in LDs polarity under conditions of ferroptosis and oxidative stress. It has shown potential in the diagnosis of NAFLD tissue and during the process of lipophagy, highlighting its value in disease diagnostics and biological research. These findings not only deepen our understanding of the mechanisms underlying NAFLD progression but also provide new tools for diagnosing and treating related diseases. [ABSTRACT FROM AUTHOR]

Interest in organic luminescent materials that show strong dual state emission (DSE) in both solution and the solid state is rapidly growing due to their widespread applications. The development of DSE luminogens (DSEgens) with multi-stimuli responsive properties capable of achieving multi-parameter detection in complicated environments remains challenging due to the lack of an explicit molecular design strategy. In this work, we devised and prepared two D-π-A-π-D-structured carbazole derivatives, PY-CZ-Pa and PY-CZ-Ta , with intramolecular charge transfer (ICT) characteristics and excellent DSE properties. Both the compounds as fluorescent probes are highly sensitive to trace amount of water and picric acid (PA) in organic solvents. The limits of detection are determined to be 0.016% (PY-CZ-Pa) or 0.040% (PY-CZ-Ta) for water and 320 nM (PY-CZ-Pa) or 538 nM (PY-CZ-Ta) for PA. Moreover, the two compounds exhibit reversible mechanofluorochromism, with spectral shifts of over 24 nm. The results presented in this work suggest that bright DSEgens with multi-stimuli responsive properties are promising materials for applications at both the molecular and aggregated levels. • Two D-π-A-π-D-structured compounds, PY-CZ-Pa and PY-CZ-Ta , have been synthesized. • Both compounds are highly emissive in both dilute solutions and the solid state. • Both compounds can sensitively detect picric acid and trace water. • Both compounds exhibit reversible mechanofluorochromism. [ABSTRACT FROM AUTHOR]

Imidazole is an important heterocyclic motif and its derivatives are widely used in many fields such as catalysis, medicine, and smart sensors. Here we report the synthesis of four imidazole derivatives (M1, M2, M3, and M4) with different fused aromatics as fluorescent sensors for picric acid (PA) detection. The four compounds with modifications of triphenylamine or tetraphenylethylene at the N1 and C2 positions of the imidazole ring exhibit typical aggregation-induced emission (AIE) properties. The single crystallography results indicate that the bright luminescence is ascribed to the rigidified molecular conformation by multiple weak interactions. As PA probes, M1–M4 show high selectivity and sensitivity in the tetrahydrofuran/water mixture (fw = 99%). The detection limits are as low as 10−9 M. Mechanism study suggests that photoinduced electron transfer (PET) is responsible for PA detection. These AIE-active imidazole derivatives have been demonstrated to be convenient and easily operating sensors for PA detection. [ABSTRACT FROM AUTHOR]

A novel luminescent liquid crystal, (2Z,2′Z)-2,2′-(1,4-phenylene)bis(3-(4-(dodecyloxy)phenyl)acrylonitrile) (PDPA), is reported, which shows green, yellow and orange colors depending on the self-assembled structure. The luminescence of PDPA can vary between those three different colors invoked by mechanical shearing and thermal annealing. Moreover, an excellent liquid crystal phase transition of PDPA is observed using polarized optical microscopy (POM) and differential scanning calorimetry (DSC) analysis. Finally, a prototype device is fabricated that demonstrates rewritable fluorescence optical recording with multistimuli luminescence tuning. [ABSTRACT FROM AUTHOR]

The development of low molecular‐weight gelators for the construction of stimuli‐responsive gels is increasing attention because of the great application potential. In this work, we report the design and synthesis of two new naphthalimide derivatives, GSSN and GN, as supramolecular organogelators. GSSN contains a disulfide bond in the molecule, while GN contains no disulfide bond. As a result, only GSSN exhibited reduction responsiveness. A series of tests, including UV‐vis, temperature‐dependent 1H NMR, XRD, and SEM, were carried out to characterize the gelation capability and probe into the gelation mechanism. Results showed that GN can gelate more organic solvents than GSSN. Both hydrogen bonding and π stacking contribute to the gelation. Due to the difference in the assembly of the organogelator molecules, the organogels formed by GSSN and GN presented distinct morphologies. Moreover, strong hydrophobicity was found in the organogel films of GSSN and GN, suggesting potential application as hydrophobic coating materials. [ABSTRACT FROM AUTHOR]

Developing and healing tissues begin as cellular condensations. Spatiotemporal changes in tissue geometry, transformations in the spatial distribution of the cells, and extracellular matrix are essential for its evolution into a functional tissue. 4D materials, 3D materials capable of geometric changes, may have the potential to recreate the aforementioned biological phenomenon. However, most reported 4D materials are non‐degradable and/or not biocompatible, limiting their application in regenerative medicine, and to date, there are no systems controlling the geometry of high density cellular condensations and differentiation. Here, 4D high cell density tissues based on shape‐changing hydrogels are described. By sequential photocrosslinking of oxidized and methacrylated alginate (OMA) and methacrylated gelatin (GelMA), bilayered hydrogels presenting controllable geometric changes without any external stimuli are fabricated. Fibroblasts and human adipose‐derived stem cells (ASCs) are encapsulated at concentrations up to 1.0 × 108 cells mL–1 in the 4D constructs, and controllable shape changes are achieved in concert with ASCs differentiated down chondrogenic and osteogenic lineages. Bioprinting of the high density cell‐laden OMA and GelMA permits the formation of more complex constructs with defined 4D geometric changes, which may further expand the promise of this approach in regenerative medicine applications. [ABSTRACT FROM AUTHOR]

Dual-state luminophores (DSEgens) that exhibit intense emission in both molecularly dispersed state and the solid state have garnered significant interest due to their versatile applications in various fields. In this study, we report the synthesis of three conformationally twisting phenothiazine-cyanostilbene conjugates, PTZ 5–7 , as bright DSEgens with intracellular charge transfer (ICT) character. Their photophysical properties in solution and the solid state are thoroughly investigated using spectroscopic measurements and quantum chemical calculations. Notably, it has been discovered that a simple modification involving anisole groups on the conjugate's flanks is highly effective in redshifting the emission by enhancing electronic conjugation and narrowing the energy gap between the ground and excited states. As a result, the introduction of two anisole groups on both flanks of the phenothiazine-cyanostilbene conjugate leads to the development of PTZ-7 , a red-emissive DSEgen with high brightness (Φ THF = 48.6 % and Φ solid = 42.3 %). Leveraging the DSE properties of these compounds, we demonstrate their effectiveness for imaging live cells across a wide concentration range in the dispersed state, as well as their mechanofluorochromic behavior in the aggregated state, exhibiting a spectral shift of over 40 nm. [Display omitted] [ABSTRACT FROM AUTHOR]

Dual-state luminogens (DSEgens) are organic luminescent molecules that exhibit strong emissions in both molecularly dispersed and aggregated states. The introduction of fluorine into organic conjugates has been shown to influence their photophysical properties, but its effect on DSEgens remains unexplored. Herein, we synthesized three naphthalimide-arylimidazole luminogens, namely NIBH , NIBPF , and NIBOF , with fluorinated or nonfluorinated phenyl groups on the pyrrole-like nitrogen. We systematically investigated their photophysical properties using spectroscopic studies, theoretical calculations, and single crystallography. Our results demonstrate that fluorine substitution in DSEgens leads to shortened electronic conjugation, highly twisted molecular conformations, and loose three-dimensional packing arrangements. Consequently, fluorinated DSEgens, such as NIBPF and NIBOF , exhibited a significant spectral blueshift and more pronounced mechanofluorochromic properties compared to the non-fluorinated NIBH. Intriguingly, NIBPF with a para-position fluorine substituent displayed relatively redshifted and stronger emission in tetrahydrofuran solutions, while showing a blueshifted and lower emission in the solid state compared to NIBOF , which has an ortho-position fluorine substituent. These findings confirm the efficacy of fluorine as a small substituent to tune the photophysical properties of DSEgens in both dilute solutions and the solid state. Furthermore, the three bright DSEgens were employed for mechanofluorochromism, trace water analysis, and live-cell imaging applications. • Three naphthalimide-arylimidazole conjugates with DSE properties are synthesized. • These DSEgens vary in fluorine substitution. • Fluorine effect on photophysical properties is systematically investigated. • Fluorine substitution is effective to tune the photophysical properties of DSEgens. • DSEgens show mechanofluorochromism, trace water detection, and live-cell imaging. [ABSTRACT FROM AUTHOR]

Hypochlorous acid (HClO) is a reactive oxygen species (ROS) that plays a critical role in numerous pathological and physiological processes. Abnormal concentrations of HClO in vivo have been closely linked to many diseases, including inflammatory disorders and cancer. In this work, an on-off fluorescent probe PTZ based on phenothiazine was synthesized for specific detection of HClO. PTZ demonstrated excellent selectivity, biocompatibility, rapid response, pH stability, and low limits of detection (5.2 nM). Furthermore, PTZ can detect both exogenous and endogenous HClO rapidly in living cells and zebrafish, which provides it with broad potential applications in life sciences. Rapid and sensitive phenothiazine-based fluorescent probe for detecting endogenous HClO in living cells and zebrafish. [Display omitted] [ABSTRACT FROM AUTHOR]

Supramolecular organogels are semi-solid materials that have garnered tremendous interest in the past two decades due to their intriguing responsiveness to external stimuli. However, the construction of supramolecular organogels often involves inconvenient dissolution-enhancement steps such as heating and sonication, which exclude the use of heat or sonication sensitive materials and limit their applications. Herein, two tritylthio-terminated gallic acid (GA) derivatives G1 and G2 , which differ subtly in the length and structure of the space that links the GA unit and the trityl thiol and are incapable of gelating organic solvents at room temperature, have been developed as pre-low molecular organic gelators (pre-LMOGs) for in situ gelation at room temperature. G1 or G2 underwent oxidative coupling reaction in the presence of iodine (I 2) and turned into LMOGs without the need of a second component, leading to effective in situ gelation. Meanwhile, the in situ generated disulfide bonds confer reduction responsiveness to the formed organogels. A variety of characterizations including UV–vis absorption, transform-infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), nuclear magnetic resonance (NMR) study, scanning electron microscopy (SEM), and theoretical calculation were employed to examine the gelation property and probe into the gelation mechanism. The difference in gelation performance of the pre-LMOGs and the in situ generated LMOGs suggests the importance of molecular flexibility in controlling the gelation behaviors. With the data, it is concluded that the gelation is driven by the collaborative contribution of multiple weak interactions, including van der Waals force, hydrogen bonding, and π stacking interaction. [Display omitted] • Two tritylthio-terminated derivatives, G1 and G2 , were synthesized as pre-LMOGs. • The subtle structural difference of G1 and G2 led to distinct gelation behaviors. • Room-temperature in situ gelation was achieved by the coupling of the pre-LMOGs. • The in situ generated organogel is reduction-responsive. [ABSTRACT FROM AUTHOR]

Bioprinting, four-dimensional materials, high cell density construct, stem cells Four-Dimensional Materials: Induction of Four-Dimensional Spatiotemporal Geometric Transformations in High Cell Density Tissues via Shape-Changing Hydrogels (Adv. Funct. Keywords: bioprinting; four-dimensional materials; high cell density construct; stem cells EN bioprinting four-dimensional materials high cell density construct stem cells 1 1 1 06/12/21 20210609 NES 210609 In article number 2010104, Eben Alsberg and co-workers report the engineering of 4D high cell density constructs (1.0 × 10 SP 8 sp cells mL SP -1 sp ) that change their shape over time by exploiting temporal differences in swelling rates between two biodegradable and cytocompatible materials. [Extracted from the article]