MDM2-Associated Clusterization-Triggered Emission and Apoptosis Induction Effectuated by a Theranostic Spiropolymer

Heteroatom-containing spiropolymers were constructed in a facile manner by a catalyst-free multicomponent spiropolymerization route. P1a2b as the most potent of these spiropolymers, demonstrates cluster-triggered emission resulting from strong interactions with the MDM2 protein. By preventing the anti-apoptotic p53/MDM2 interaction, P1a2b triggers apoptosis in cancerous cells, while demonstrating a good biocompatibility and non-toxicity in non-cancerous cells. The combined results from solution and cell-based cluster-triggered emission studies, docking, protein expression experiments and cytotoxicity data strongly support the MDM2-binding hypothesis and indicate a potential application as a fluorescent cancer marker as well as therapeutic for this spiropolymer.     

Target‐Selective Fluorescence Imaging and Photocytotoxicity against H2O2 High‐Expressing Cancer Cells Using a Photoactivatable Theranostic Agent

A purpose‐designed and synthesized H₂O₂‐reactive and photoactivatable theranostic agent 1 consisting of 1) an arylboronic acid moiety, 2) pro‐fluorophore moiety, and 3) photoactivatable moiety (photosensitizer), selectively and effectively reacted with H₂O₂ while simultaneously releasing resorufin for fluorescence detection under neutral aqueous conditions. In addition, 1 was cell‐permeable, and exhibited effective photocytotoxicity against fluorescently visualized cells only upon photoirradiation. The results also showed that 1 produced a selective fluorescence response to H₂O₂, even in living cultured cells.     

Transient and Persistent Room‐Temperature Mechanoluminescence from a White‐Light‐Emitting AIEgen with Tricolor Emission Switching Triggered by Light

Persistent luminescence from purely organic materials is basically triggered by light and electricity, which largely confines its practical applications. A purely organic AIEgen exhibits not only persistent photoluminescence, but also transient and persistent room‐temperature mechanoluminescence. By simply turning on and off a UV lamp, tricolor emission switching between blue, white, and yellow was achieved. The data from single‐crystal structure analysis and theoretical calculation suggest that mechanism of the observed persistent mechanoluminescence (pML) is correlated with the strong spin–orbit coupling of the bromine atom, as well as the formation of H‐aggregates and restriction of intramolecular motions in noncentrosymmetric crystal structure. These results outline a fundamental principle for the development of new pML materials, providing an important step forward in expanding the application scope of persistent luminescence.     

An Intracellular H2O2‐Responsive AIEgen for the Peroxidase‐Mediated Selective Imaging and Inhibition of Inflammatory Cells

Inflammatory cells have gained widespread attention because inflammatory diseases increase the risk for many types of cancer. Therefore, it is urgent and important to implement detection and treatment methods for inflammatory cells. Herein, we constructed a theranostic probe with aggregation‐induced emission (AIE) characteristics, in which tetraphenylethene (TPE) was modified with two tyrosine (Tyr) moieties. Owing to the H₂O₂‐dependent, enzyme‐catalyzed dityrosine formation, Tyr‐containing TPE ( TT ) molecules crosslink through dityrosine linkages to induce the formation of hydrophobic aggregates, activating the AIE process in inflammatory cells that contain H₂O₂ and overexpress myeloperoxidase. The emission turn‐on resulting from the crosslinking of TT molecules could be used to distinguish between inflammatory and normal cells. Moreover, the massive TT aggregates induced mitochondria damage and cell apoptosis. This study demonstrates that the H₂O₂‐responsive peroxidase‐activated AIEgen holds great promise for inflammatory‐cell selective imaging and inhibition.     

Photophysical Properties of Emissive Pyrido[3,2‐c]carbazole Derivatives and Apoptosis Induction: Development towards Theranostic Agents in Response to Light Stimulus

Pyridocarbazole moieties are present in many natural products, such as olivacine and ellipticine, and their derivatives are well‐known anticancer agents. To develop functional therapeutic and diagnostic compounds, three emissive pyrido[3,2‐c]carbazole derivatives, PC‐X , containing secondary or tertiary amine groups, were synthesized from an aminoquinoline derivative using a palladium complex as the catalyst. X‐ray diffraction analyses revealed that PC‐X showed highly planar structures between the pyridine ring and the carbazole framework, exhibiting high fluorescence intensities along with solvatochromic behavior. Imaging of HeLa cells treated with PC‐X showed no specific accumulation into the organelles; however, a comparative examination showed that the accumulation in mitochondria was the highest as compared to nuclei and lysosomes. Cytotoxicity analysis using HeLa cells showed that PC‐H, containing a secondary amine group showed the highest cytotoxicity (IC₅₀≈20 μm ) as compared to another PC‐X having a tertiary amine group. Colocalization with MitoTracker, a typical mitochondrial staining dye, showed apoptosis‐like behavior with remarkable appearance of blebbing during irradiation with near UV light (403 nm), suggesting that the PC‐H may not only behave as a fluorescence probe for the imaging organelles, but also as a therapeutic agent for inducing apoptosis in HeLa cells, thereby functioning as a theranostic agent.     

Theranostic Layer‐by‐Layer Nanoparticles for Simultaneous Tumor Detection and Gene Silencing

Layer‐by‐layer nanoparticles (NPs) are modular drug delivery vehicles that incorporate multiple functional materials through sequential deposition of polyelectrolytes onto charged nanoparticle cores. Herein, we combined the multicomponent features and tumor targeting capabilities of layer‐by‐layer assembly with functional biosensing peptides to create a new class of nanotheranostics. These NPs encapsulate a high weight percentage of siRNA while also carrying a synthetic biosensing peptide on the surface that is cleaved into a urinary reporter upon exposure to specific proteases overexpressed in the tumor microenvironment. Importantly, this biosensor reports back on a molecular signature characteristic to metastatic tumors and associated with poor prognosis, MMP9 protease overexpression. This nanotheranostic mediates noninvasive urinary‐based diagnostics in mouse models of three different cancers with simultaneous gene silencing in flank and metastatic mouse models of ovarian cancer.     

Unveiling the “Three‐Finger Pharmacophore” Required for p53–MDM2 Inhibition by Saturation‐Transfer Difference (STD) NMR Initial Growth‐Rates Approach

Inhibitors of the p53‐MDM2 protein–protein interaction are emerging as a new and validated approach to treating cancer. Herein, we describe the synthesis and inhibitory evaluation of a series of isoquinolin‐1‐one analogues, and highlight the utility of an initial growth‐rates saturation‐transfer difference (STD) NMR approach supported by protein–ligand docking to investigate p53‐MDM2 inhibition. The approach is illustrated by the study of compound 1 , providing key insights into the binding mode of this kind of MDM2 ligands and, more importantly, readily unveiling the previously proposed three‐finger pharmacophore requirement for p53‐MDM2 inhibition.     

Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes

Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca²⁺-independent phospholipase A₂ beta (iPLA₂β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA₂β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA₂β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA₂β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA₂β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA₂β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA₂β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.     

pH‐Triggered Sustained Drug Delivery from a Polymer Micelle having the β‐Thiopropionate Linkage

The synthesis, micellar aggregation, and pH‐triggered intracellular drug delivery ability of an amphiphilic statistical copolymer (P2) are studied. Two methacrylate derivatives, one containing a hydrophilic pendant and the other containing a hydrophobic pendant chain, are copolymerized to produce P2. The hydrophobic pendant chain is linked to the polymer backbone by a β‐thiopropionate linkage, known to undergo slow hydrolysis at mild acidic pH. P2 forms a multimicellar cluster in water with a critical aggregation concentration of 0.02 mg mL⁻¹ and encapsulates a hydrophobic guest such as pyrene, Nile red, or the anti‐cancer drug doxorubicin (Dox). Sustained release of the entrapped Dox (80% after 100 h) is noticed at pH 5.2, while release is significantly slower (35% after 100 h) at pH 7.4. Acidic hydrolysis of the β‐thiopropionate linkage leading to the reduction of the hydrophobicity is established as the cause for micellar disassembly and triggered drug release. Cell‐culture studies with the human breast cancer cell line, MCF‐7, reveal biocompatibility of P2 (below 150 μg mL⁻¹). It is further tested for intracellular delivery of Dox. MCF‐7 cells remain healthy at pH 7.4 but become unhealthy at pH 5.2 when treated with a Dox‐loaded P2 micelles.

     

Induction of Strong Long‐Lived Room‐Temperature Phosphorescence of N‐Phenyl‐2‐naphthylamine Molecules by Confinement in a Crystalline Dibromobiphenyl Matrix

The design and preparation of metal‐free organic materials that exhibit room‐temperature phosphorescence (RTP) is a very attractive topic owing to potential applications in organic optoelectronic devices. Herein, we present a facile approach to efficient and long‐lived organic RTP involving the doping of N‐phenylnaphthalen‐2‐amine (PNA) or its derivatives into a crystalline 4,4′‐dibromobiphenyl (DBBP) matrix. The resulting materials showed strong and persistent RTP emission with a quantum efficiency of approximately 20 % and a lifetime of a few to more than 100 milliseconds. Bright white dual emission containing blue fluorescence and yellowish‐green RTP from the PNA‐doped DBBP crystals was also confirmed by Commission Internationale de l'Eclairage (CIE) coordinates of (x=0.29–0.31, y=0.38–0.41).     

Crystal Structure and Characterization of a Double‐helical‐chain Coordination Polymer Zinc Complex Constructed by Flexible Dicarboxylate Ligand 2‐Nitro‐benzene‐1,4‐di(oxyacetate) and Rigid 2,2′‐Bipyridine Ligand

A novel double‐helical‐chain coordination polymer [Zn(nbdoa)(2,2′‐bipy)(H₂O)]_n constructed by flexible 2‐nitro‐benzene‐1,4‐di(oxyacetate) ligand and rigid 2,2′‐bipyridine ligand was obtained by hydrothermal reaction. The crystal structure demonstrates that there is a double‐helical chain with an inner channel running parallel to the helix axis without any interpenetration, which is connected to network via π‐π stacking and hydrogen bond interactions. The thermal analysis shows that the infinite helical structure is stable up to 536 K. The luminescence property is investigated and the complex shows photoluminescence in the solid state at room temperature.     

Efficient NIR‐Light Emission from Solid‐State Complexes of Boron Difluoride with 2′‐Hydroxychalcone Derivatives

This article describes a series of nine complexes of boron difluoride with 2′‐hydroxychacone derivatives. These dyes were synthesized very simply and exhibited intense NIR emission in the solid state. Complexation with boron was shown to impart very strong donor–acceptor character into the excited state of these dyes, which further shifted their emission towards the NIR region (up to 855 nm for dye 5 b , which contained the strongly donating triphenylamine group). Strikingly, these optical features were obtained for crystalline solids, which are characterized by high molecular order and tight packing, two features that are conventionally believed to be detrimental to luminescence in organic crystals. Remarkably, the emission of light from the π‐stacked molecules did not occur at the expense of the emission quantum yield. Indeed, in the case of pyrene‐containing dye 4 , for example, a fluorescence quantum yield of about 15 % with a fluorescence emission maximum at 755 nm were obtained in the solid state. Moreover, dye 3 a and acetonaphthone‐based compounds 1 b , 2 b , and 3 b showed no evidence of degradation as solutions in CH₂Cl₂ that contained EtOH. In particular, solutions of brightly fluorescent compound 3 a (brightness: ε×Φ_f=45 000 M ^?1 cm^?1) could be stored for long periods without any detectable changes in its optical properties. All together, these new dyes possess a set of very interesting properties that make them promising solid‐state NIR fluorophores for applications in materials science.     

Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells

MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis independent of p53. Despite the importance of the MDM2 RING domain in p53 regulation and cancer development, small molecule inhibitors targeting the E3 ligase activity of MDM2-MDM4 are poorly explored. Here, we describe the synthesis and characterization of quinolinol derivatives for the identification of analogs that are capable of targeting the MDM2-MDM4 heterodimer E3 ligase and inducing apoptosis in cells. The structure-activity-relationship (SAR) study identified structural moieties critical for the inhibitory effects toward MDM2-MDM4 E3 ligase, the targeted degradation of MDM4 and FTH1 in cells, and anti-proliferation activity. Lead optimization led to the development of compound MMRi71 with improved activity. In addition to accumulating p53 proteins in wt-p53 bearing cancer cells as expected of any MDM2 inhibitors, MMRi71 effectively kills p53-null leukemia cells, an activity that conventional MDM2-p53 disrupting inhibitors lack. This study provides a prototype structure for developing MDM4/FTH1 dual-targeting inhibitors as potential cancer therapeutics.     

Strong and Reversible Circularly Polarized Luminescence Emission of a Chiral 1,8‐Naphthalimide Fluorophore Induced by Excimer Emission and Orderly Aggregation

Four chiral 1,2‐diaminocyclohexane (DACH)‐based molecules (R,R/S,S‐ 2 and R,R/S,S‐ 4 ) incorporating 1,8‐naphthalimide fluorophores exhibit strong circularly polarized luminescence (CPL) emission signals in common organic solvents. Interestingly, the reversed CPL signals can be observed in the aggregated state, which is due to the orderly aggregation.     

Revealing Crystallization‐Induced Blue‐Shift Emission of a Di‐Boron Complex by Enhanced Photoluminescence and Electrochemiluminescence

Elucidating the effects of crystallization‐induced blue‐shift emission of a newly synthesized di‐boron complex (DBC) by enhanced photoluminescence (PL) and electrochemiluminescence (ECL) in the annihilation pathway was realized for the first time. The 57 nm blue‐shift and great enhancement in the crystalline lattice relative to the DBC solution were attributed to the restriction of intramolecular rotation (RIR) and confirmed by PL imaging, X‐ray diffraction, as well as DFT calculations. It was discovered that ECL at crystalline film/solution interfaces can be further enhanced by means of both co‐reactant route and RIR. The RIR contributions with co‐reactant increased ECL up to 5 times more. Very interestingly, the co‐reactant system was found to give off a red‐shifted light emission. Mechanistic studies reveal that a difference between location of the ECL in the co‐reactant route and that in the annihilation pathway leads to an alternative emission wavelength.     

White‐Light Emission Strategy of a Single Organic Compound with Aggregation‐Induced Emission and Delayed Fluorescence Properties

A novel white‐light‐emitting organic molecule, which consists of carbazolyl‐ and phenothiazinyl‐substituted benzophenone (OPC) and exhibits aggregation‐induced emission‐delayed fluorescence (AIE‐DF) and mechanofluorochromic properties was synthesized. The CIE color coordinates of OPC were directly measured with a non‐doped powder, which presented white‐emission coordinates (0.33, 0.33) at 244 K to 252 K and (0.35, 0.35) at 298 K. The asymmetric donor–acceptor–donor′ (D‐A‐D′) type of OPC exhibits an accurate inherited relationship from dicarbazolyl‐substituted benzophenone (O2C, D‐A‐D) and diphenothiazinyl‐substituted benzophenone (O2P, D′‐A‐D′). By purposefully selecting the two parent molecules, that is, O2C (blue) and O2P (yellow), the white‐light emission of OPC can be achieved in a single molecule. This finding provides a feasible molecular strategy to design new AIE‐DF white‐light‐emitting organic molecules.