Out-of-Plane Ferroelectricity in Two-Dimensional 1T‴-MoS2 Above Room Temperature.

Two-dimensional (2D) molybdenum disulfide (MoS2), one of the most extensively studied van der Waals (vdW) materials, is a significant candidate for electronic materials in the post-Moore era. MoS2 exhibits various phases, among which the 1T‴ phase possesses noncentrosymmetry. 1T‴-MoS2 was theoretically predicted to be ferroelectric a decade ago, but this has not been experimentally confirmed until now. Here, we have prepared high-purity 2D 1T‴-MoS2 crystals and experimentally confirmed the room-temperature out-of-plane ferroelectricity. The noncentrosymmetric crystal structure in 2D 1T‴-MoS2 was convinced by atomically resolved transmission electron microscopic imaging and second harmonic generation (SHG) measurements. Further, the ferroelectric polarization states in 2D 1T‴-MoS2 can be switched using piezoresponse force microscopy (PFM) and electrical gating in field-effect transistors (FETs). The ferroelectric-to-paraelectric transition temperature is measured to be about 350 K. Theoretical calculations have revealed that the ferroelectricity of 2D 1T‴-MoS2 originates from the intralayer charge transfer of S atoms within the layer. The discovery of intrinsic ferroelectricity in the 1T‴ phase of MoS2 further enriches the properties of this important vdW material, providing more possibilities for its application in the field of next-generation electronic devices.

Mesoporous carbon hemispheres integrated with Fe-Gd nanoparticles for potential MR/PA imaging-guided photothermal therapy.

Asymmetric carbon has emerged as an important material to enrich morphologies as well as enhance functions for bioapplications. Here, asymmetric mesoporous carbon hemispheres (CHS) integrated with γ-Fe2O3 and GdPO4 (Fe-Gd) nanoparticles are proposed and prepared for potential imaging-guided photothermal therapy (PTT). Interestingly, Fe-Gd/CHS contributes to an almost 1.5 times enhancement in light harvesting and photothermal conversion efficiency as compared with its corresponding spherical analogue. The possible underlying mechanism is discussed in view of the unique asymmetric structure-featured carbon. Further identification of the inherited photoacoustic (PA) and magnetic resonance (MR) imaging properties leads to the consequent in vivo evaluation of its imaging and PTT performances, which demonstrates its capability as a function-integrated system for potential theranostics.

Self-Healing Hydrogen-Bonded Organic Frameworks for Low-Concentration Ammonia Capture.

The self-healing behavior has been extensively used in intelligent sensing systems capable of molecular recognition. However, most rigid crystalline frameworks, once collapsed under external stimuli like pressure, heat, or vacuum, could hardly recover to their crystalline phases under ambient conditions. Here, we report the self-healing of a new microporous hydrogen-bonded organic framework, FDU-HOF-3 (FDU = Fudan University), for ammonia (NH3) capture and compared it with the established mesoporous HOF-101. With the introduction of low-concentration NH3 into the pores, the HOFs became disordered but were then simply heated under a vacuum to return to their original crystalline states after NH3 removal. Close characterizations revealed that the repeatable self-healing behavior of these HOFs was achieved due to the COOH-NH3 acid-base interactions accompanied by the breaking and regeneration of complementary COOH-COOH hydrogen bonds. FDU-HOF-3 showed a record-capturing capability for low-concentration NH3 (8.13 mmol/g at 25 mbar) among all HOFs and displayed a quick photocurrent decrease after exposure to 250 ppm NH3 for less than 10 s. These self-healing HOFs were used to capture and release NH3 for over 10 cycles without any decrease in the adsorption capacities.

Systematical Evaluation of the Structure-Cardiotoxicity Relationship of 7-Azaindazole-based PI3K Inhibitors Designed by Bioisosteric Approach.

A growing concern of cardiotoxicity induced by PI3K inhibitors has raised the requirements to evaluate the structure-cardiotoxicity relationship (SCR) in the development process of novel inhibitors. Based on three bioisosteric 7-azaindazole-based candidate inhibitors namely FD269, FD268 and FD274 that give same order of inhibitory concentration 50% (IC50) magnitude against PI3Ks, in this work, we proposed to systematically evaluate the SCR of 7-azaindazole-based PI3K inhibitors designed by bioisosteric approach. The 24-h lethal concentrations 50% (LC50) of FD269, FD268 and FD274 against zebrafish embryos were 0.35, 4.82 and above 50 µM (not detected), respectively. Determination of the heart rate, pericardial and yolk-sac areas and vascular malformation confirmed the remarkable reduction in the cardiotoxicity of from FD269 to FD268 and to FD274. The IC50s of all three compounds against the hERG channel were tested on the CHO cell line that constitutively expressing hERG channel, which were all higher than 20 µM. The transcriptomic analysis revealed that FD269 and FD268 induced the up-regulation of noxo1b, which encodes a subunit of an NADPH oxidase evoking the oxidative stress. Furthermore, immunohistochemistry tests confirmed the structure-dependent attenuation of the overproduction of ROS and cardiac apoptosis. Our results verified the feasibility of bioisosteric replacement to attenuate the cardiotoxicity of 7-azaindazole-based PI3K inhibitors, suggesting that the screening for PI3K inhibitors with both high potency and low cardiotoxicity from bioisosteres would be a beneficial trial.

Multivariate Hydrogen-Bonded Organic Frameworks with Tunable Permanent Porosities for Capture of a Mustard Gas Simulant.

Precise synthesis of topologically predictable and discrete molecular crystals with permanent porosities remains a long-term challenge. Here, we report the first successful synthesis of a series of 11 isoreticular multivariate hydrogen-bonded organic frameworks (MTV-HOFs) from pyrene-based derivatives bearing -H, -CH3 , -NH2 and -F groups achieved by a shape-fitted, π-π stacking self-assembly strategy. These MTV-HOFs are single-crystalline materials composed of tecton, as verified by single-crystal diffraction, nuclear magnetic resonance (NMR) spectra, Raman spectra, water sorption isotherms and density functional theory (DFT) calculations. These MTV-HOFs exhibit tunable hydrophobicity with water uptake starting from 50 to 80 % relative humidity, by adjusting the combinations and ratios of functional groups. As a proof of application, the resulting MTV-HOFs were shown to be capable of capturing a mustard gas simulant, 2-chloroethyl ethyl sulfide (CEES) from moisture. The location of different functional groups within the pores of the MTV-HOFs leads to a synergistic effect, which resulted in a superior CEES/H2 O selectivity (up to 94 %) compared to that of the HOFs with only pure component and enhanced breakthrough performance (up to 4000 min/g) when compared to benchmark MOF materials. This work is an important advance in the synthesis of MTV-HOFs, and provides a platform for the development of porous molecular materials for numerous applications.

A Solution-Processable Porphyrin-Based Hydrogen-Bonded Organic Framework for Photoelectrochemical Sensing of Carbon Dioxide.

Detecting CO2 in complex gas mixtures is challenging due to the presence of competitive gases in the ambient atmosphere. Photoelectrochemical (PEC) techniques offer a solution, but material selection and specificity remain limiting. Here, we constructed a hydrogen-bonded organic framework material based on a porphyrin tecton decorated with diaminotriazine (DAT) moieties. The DAT moieties on the porphyrin molecules not only facilitate the formation of complementary hydrogen bonds between the tectons but also function as recognition sites in the resulting porous HOF materials for the selective adsorption of CO2 . In addition, the in-plane growth of FDU-HOF-2 into anisotropic molecular sheets with large areas of up to 23000 µm2 and controllable thickness between 0.298 and 2.407 µm were realized in yields of over 89 % by a simple solution-processing method. The FDU-HOF-2 can be directly grown and deposited onto different substrates including silica, carbon, and metal oxides by self-assembly in situ in formic acid. As a proof of concept, a screen-printing electrode deposited with FDU-HOF-2 was fabricate as a label-free photoelectrochemical (PEC) sensor for CO2 detection. Such a signal-off PEC sensor exhibits low detection limit for CO2 (2.3 ppm), reusability (at least 30 cycles), and long-term working stability (at least 30 days).

Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer.

Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

Discovery of a photosensitizing PI3K inhibitor for tumor therapy: Design, synthesis and in vitro biological evaluation.

In drug development, optical triggering of cancer therapy is increasingly used. Herein, we report a novel photosensitive PI3K inhibitor FD2157, which bears a photoprotecting moiety and can be efficiently cleaved with enhanced anticancer activity upon short-term light irradiation. In biological assessment, FD2157 exhibited remarkably enhanced anticancer activity in inhibition of PI3K pathway against melanoma cell lines upon light irradiation (4 min). Hence, this photosensitive PI3K inhibitor FD2157 may represent a valuable tool compound for studying the PI3K pathway and further optimization toward light-triggered cancer treatment.

Reticular Chemistry of the Fcu-Type Gd(III)-Doped Metal-Organic Framework for T1 -Weighted Magnetic Resonance Imaging.

Nanoscale metal-organic frameworks (nanoMOFs) are emerging as an important class of nanomaterials for the systematical investigation of biomedically relevant structure-property relationship (SPR) due to their highly tailorable features. In this work, the reticular chemistry approach is shown to explore the SPR of a fcu-type Zr(IV)-nanoMOF for T1 -weighted magnetic resonance imaging (MRI). Isoreticular replacement of the eight-coordinated square-antiprismatic Zr(IV) by nine-coordinated Gd(III) brings a stoichiometric water capped on the square-antiprismatic site, enabling the relaxation transfer in the inner-sphere, giving the r1 value of 4.55 mM-1 ·s-1 at the doping ratio of Gd : Zr = 1 : 1. Then, these isoreticular engineering studies provide feasible ways to facilitate the relaxation transfer in the second- and outer-sphere of the Gd(III)-doped Zr-oxo cluster for the relaxation respectively. Finally, these in vitro and in vivo MRI studies revealed that the Gd(III)-doped Zr-oxo cluster aggregated underlying the fcu-type framework surpasses its discrete molecular cluster for MRI. These results demonstrated that there is plenty of room inside MOFs for T1 -weighted MRI by reticular chemistry.

Discovery of a high potent PIM kinase inhibitor for acute myeloid leukemia based on N-pyridinyl amide scaffold by optimizing the fragments toward to Lys67 and Asp128/Glu171.

Despite the recent development of PIM inhibitors based on N-(pyridin-3-yl)acetamide scaffold for acute myeloid leukemia (AML), the structural-activity relationship (SAR) associated with the effects of positional isomerization of N toward to Lys67 and freedom of solvent fragment toward to Asp128/Glu171 still remains an open question. In this work, a structurally novel compound based on N-pyridinyl amide was designed by fragment hybridization and then our SAR exploration revealed that the positional isomerization would lead to a decrease in activity, while increase of the freedom of solvent fragment by breaking the intramolecular hydrogen bond unprecedentedly leads to an increase in activity. These studies finally resulted in the screening out of a potent PIM inhibitor FD1024 (compound 24) which exerts strong antiproliferative activity against the tested AML cell lines and achieves profound antitumor efficacy in mice at well-tolerated dose schedules.

Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia.

PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC50 values against PI3Kα/ß/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC50 values of 0.092 µM and 0.084 µM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

Mechanistic investigation of the influence of defects on armchair unburned carbon for PbCl2 adsorption.

As the largest consumer of coal energy, coal-fired power plants emit large amounts of PbCl2 each year, which is of wide concern due to its high toxicity, global migration, and accumulation. Unburned carbon is considered a promising adsorbent for effective PbCl2 removal. However, there is a problem that the current unburned carbon model cannot show the structure of carbon defects on the actual unburned carbon surface. Therefore, it is important to construct defective unburned carbon models with practical significance. In addition, the adsorption mechanism of PbCl2 by an unburned model is not studied deeply enough and the reaction mechanism is not clear yet. This has seriously affected the development of effective adsorbents. To reveal the adsorption mechanism of PbCl2 on unburned carbon, the adsorption mechanism of PbCl2 on defective unburned carbon surfaces was analyzed by using the density flooding theory to investigate the adsorption process of PbCl2 on different unburned carbon models. This will provide theoretical guidance for the design and development of adsorbents for the removal of PbCl2 from coal-fired power plants.

Gelothermal Synthesis of Monodisperse MIL-88A Nanoparticles with Tunable Sizes and Metal Centers for Potential Bioapplications.

Developing novel synthetic strategies to downsize metal-organic frameworks (MOFs) from polydisperse crystals to monodisperse nanoparticles is of great importance for their potential bioapplications. In this work, a novel synthetic strategy termed gelothermal synthesis is proposed, in which coordination polymer gel is first prepared and followed by a thermal reaction to give the monodisperse MOF nanoparticles. This novel synthetic strategy successfully leads to the isolation of Materials of Institute Lavoisier (MIL-88), Cu(II)-fumarate MOFs (CufumDMF), and Zeolitic Imidazolate Frameworks (ZIF-8) nanoparticles. Focused on MIL-88A, the studies reveal that the size can be well-tuned from nanoscale to microscale without significant changes in polydispersity index (PDI) even in the case of in situ metal substitution. A possible mechanism is consequently proposed based on extensive studies on the gelothermal condition including sol-gel chemistry, thermal condition, kinds of solvents, and so on. The unique advantages of monodisperse MIL-88A nanoparticles over polydisperse ones are further demonstrated in terms of in vitro magnetic resonance imaging (MRI), cellular uptake, and drug-carrying properties.

Photo-Fenton self-cleaning carbon fibers membrane supported with Zr-MOF@Fe2O3 for effective phosphate removal from algae-rich water.

Adsorbents featuring abundant binding sites and high affinity to phosphate have been used to resolve water eutrophication. However, most of the developed adsorbents were focused on improving the adsorption ability of phosphate but ignored the effect of biofouling on the adsorption process especially used in the eutrophic water body. Herein, a novel MOF-supported carbon fibers (CFs) membrane with high regeneration and antifouling capability, was prepared by in-situ synthesis of well-dispersed MOF on CFs membrane, to remove phosphate from algae-rich water. The hybrid UiO-66-(OH)2@Fe2O3@CFs membrane exhibits a maximum adsorption capacity of 333.3 mg g-1 (pH 7.0) and excellent selectivity for phosphate sorption over coexisting ions. Moreover, the Fe2O3 nanoparticles anchored on the surface of UiO-66-(OH)2 through 'phenol-Fe(III)' reaction can endow the membrane with the robust photo-Fenton catalytic activity, which improves long-term reusability even under algae-rich condition. After 4 times photo-Fenton regenerations, the regeneration efficiency of the membrane could remain 92.2%, higher than that of hydraulic cleaning (52.6%). Moreover, the growth of C. pyrenoidosa was significantly reduced by 45.8% within 20 days via metabolism inhibition due to membrane-induced P-deficient conditions. Hence, the developed UiO-66-(OH)2@Fe2O3@CFs membrane holds significant prospects for large-scale application in phosphate sequestration of eutrophic water bodies.

Van der Waals Ferroelectric Semiconductor Field Effect Transistor for In-Memory Computing.

In-memory computing is a highly efficient approach for breaking the bottleneck of von Neumann architectures, i.e., reducing redundant latency and energy consumption during the data transfer between the physically separated memory and processing units. Herein we have designed a in-memory computing device, a van der Waals ferroelectric semiconductor (InSe) based metal-oxide-ferroelectric semiconductor field-effect transistor (MOfeS-FET). This MOfeS-FET integrates memory and logic functions in the same material, in which the out-of-plane (OOP) ferroelectric polarization in InSe is used for data storage and the semiconducting property is used for the logic computation. The MOfeS-FET shows a long retention time with high on/off ratios (>106), high program/erase (P/E) ratios (103), and stable cyclic endurance. Moreover, inverter, programmable NAND, and NOR Boolean logic operations with nonvolatile storage of the results have all been demonstrated using our approach. These findings highlight the potential of van der Waals ferroelectric semiconductor-based MOfeS-FETs in the in-memory computing and their potential of achieving size scaling beyond Moore's law.

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer.

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is overexpressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3Kδ inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 µM and 3.7 µM, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3Kδ inhibitor and is worthy of further profiling.

Hybrid Nanomaterials for Cancer Immunotherapy.

Nano-immunotherapy has been recognized as a highly promising strategy for cancer treatment in recent decades, which combines nanotechnology and immunotherapy to combat against tumors. Hybrid nanomaterials consisting of at least two constituents with distinct compositions and properties, usually organic and inorganic, have been engineered with integrated functions and enormous potential in boosting cancer immunotherapy. This review provides a summary of hybrid nanomaterials reported for cancer immunotherapy, including nanoscale metal-organic frameworks, metal-phenolic networks, mesoporous organosilica nanoparticles, metallofullerene nanomaterials, polymer-lipid, and biomacromolecule-based hybrid nanomaterials. The combination of immunotherapy with chemotherapy, chemodynamic therapy, radiotherapy, radiodynamic therapy, photothermal therapy, photodynamic therapy, and sonodynamic therapy based on hybrid nanomaterials is also discussed. Finally, the current challenges and the prospects for designing hybrid nanomaterials and their application in cancer immunotherapy are outlined.

A General Strategy for the Synthesis of Hierarchically Ordered Metal-Organic Frameworks with Tunable Macro-, Meso-, and Micro-Pores.

Hierarchically ordered porous materials with tailored and inter-connected macro-, meso-, and micro-pores would facilitate the heterogeneous adsorption and catalysis processes for a wide range of applications but remain a challenge for synthetic chemists. Here, a general and efficient strategy for the synthesis of inverse opal metal-organic frameworks (IO MOFs) with a tunable size of macro-, meso-, and micro-pores is reported. The strategy is based on the step-wise template formation, precursor infiltration, solvo-thermal reaction, and chemical etching. As a proof of the general applicability of this strategy, a series of inverse opal zirconium-based MOFs with intrinsic micro- and/or meso-pores, including UiO-66, MOF-808, NU-1200, NU-1000 and PCN-777, and tunable macropores (1 µm, 2 µm, 3 µm, 5 µm, and 10 µm), have been prepared with outstanding yields. These IO MOFs demonstrate significantly enhanced absorption rates and faster initial hydrolysis rates for organophosphorus (OPs) aggregates compared to those of the pristine MOFs. This work paves the way for the further development of hierarchically ordered MOFs for advanced applications.

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia.

Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.

A core/shell nanogenerator achieving pH-responsive nitric oxide release for treatment of infected diabetic wounds.

Nitric oxide is critical for eliminating infection and promoting regeneration in diabetic wounds. However, clinical uses of nitric oxide are limited by its high activity and lack of specificity in targeting infections. Herein, we develop an intelligent nitric oxide nanogenerator comprising isosorbide dinitrate (ISDN)-coated copper sulfide (CuS)/calcium carbonate (CaCO3) core/shell nanoparticles (CuS@CaCO3-ISDN) to target the acidic microenvironment of the infected diabetic wounds. Meaningfully, triggered by acid decomposition of CaCO3, this nanogenerator can achieve a responsive and accelerated release of nitric oxide from ISDN through enzyme-mimicking redox processes that involve CuS nanoparticles and then inactivate biofilm bacteria through the pathways of oxidative stress and disruption of adenosine triphosphate (ATP)-related energy metabolism. Moreover, after eliminating the infection, the pH-responsive release of nitric oxide can promote the proliferation of blood vessels and tissue regeneration and accelerate diabetic wound closure. This study expands the use of nitric oxide donors in wound treatment by developing the enzyme-mimicking release strategy, and the pH-responsive core/shell nanogenerator is promising for a variety of anti-infection therapeutic applications.