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2D single-phase multiferroic materials with the coexistence of electric and spin polarization offer a tantalizing potential for high-density multilevel data storage. One of the current limitations for application is the scarcity of the materials, especially those combine ferromagnetism and ferroelectricity at high temperatures. Here, robust ferrimagnetism and ferroelectricity in 2D É-Fe2O3 samples with both single-crystalline and polycrystalline form are demonstrated. Interestingly, the polycrystalline nanosheets also exhibit easily switchable ferroelectric polarizations comparable to that of single crystals. The existence of grain boundary does not hinder the switching and retention of ferroelectric polarization. Furthermore, the É-Fe2O3 nanosheets show ferrimagnetic and ferroelectric Curie temperatures up to 800 K, which reaches record highs in 2D single-phase multiferroic materials. This work provides important progress in the exploration of 2D high-temperature single-phase multiferroics for potentially compact high-temperature information nanodevices.
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Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 µM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2-symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.
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Antígeno B7-H1 , Desenho de Fármacos , Receptor de Morte Celular Programada 1 , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/síntese química , Células Jurkat , Simulação de Acoplamento Molecular , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Animais , Benzotiazóis/farmacologia , Benzotiazóis/química , Benzotiazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/químicaRESUMO
Elastic polymer-based conductive composites (EPCCs) are of great potential in the field of flexible sensors due to the advantages of designable functionality and thermal and chemical stability. As one of the popular choices for sensor electrodes and sensitive materials, considerable progress in EPCCs used in sensors has been made in recent years. In this review, we introduce the types and the conductive mechanisms of EPCCs. Furthermore, the recent advances in the application of EPCCs to sensors are also summarized. This review will provide guidance for the design and optimization of EPCCs and offer more possibilities for the development and application of flexible sensors.
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Alzheimer's disease (AD), a progressive neurodegenerative disorder, has garnered increased attention due to its substantial economic burden and the escalating global aging phenomenon. Amyloid-ß deposition is a key pathogenic marker observed in the brains of Alzheimer's sufferers. Based on real-time, safe, low-cost, and commonly used, near-infrared fluorescence (NIRF) imaging technology have become an essential technique for the detection of AD in recent years. In this work, NIRF probes with hemicyanine structure were designed, synthesized and evaluated for imaging Aß aggregates in the brain. We use the hemicyanine structure as the parent nucleus to enhance the probe's optical properties. The introduction of PEG chain is to improve the probe's brain dynamice properties, and the alkyl chain on the N atom is to enhance the fluorescence intensity of the probe after binding to the Aß aggregates as much as possible. Among these probes, Z2, Z3, Z6, X3, X6 and T1 showed excellent optical properties and high affinity to Aß aggregates (Kd = 24.31 â¼ 59.60 nM). In vitro brain section staining and in vivo NIRF imaging demonstrated that X6 exhibited superior discrimination between Tg mice and WT mice, and X6 has the best brain clearance rate. As a result, X6 was identified as the optimal probe. Furthermore, the docking theory calculation results aided in describing X6's binding behavior with Aß aggregates. As a high-affinity, high-selectivity, safe and effective probe of targeting Aß aggregates, X6 is a promising NIRF probe for in vivo detection of Aß aggregates in the AD brain.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Carbocianinas , Desenho de Fármacos , Corantes Fluorescentes , Imagem Óptica , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/análise , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Animais , Carbocianinas/química , Carbocianinas/síntese química , Camundongos , Estrutura Molecular , Humanos , Agregados Proteicos , Relação Estrutura-Atividade , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Relação Dose-Resposta a DrogaRESUMO
Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor.
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Antineoplásicos , Apoptose , Proliferação de Células , Quinase 9 Dependente de Ciclina , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores de Proteínas Quinases , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Humanos , Ligantes , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Descoberta de Drogas , Animais , Células HCT116RESUMO
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment. The best-performing derivative H10 showed good selectivity for multiple isoforms of the HDAC family. The structural analysis and structure-activity relationship studies of H10 will contribute to optimizing the binding mode of the new molecules. The pharmacological mechanism of H10 to inhibit pulmonary fibrosis was validated, and its ability to inhibit the IPF phenotype was also demonstrated. Moreover, H10 showed satisfactory metabolic stability. The efficacy of H10 was also determined in a mouse model of bleomycin-induced pulmonary fibrosis. The results highlighted in this paper may provide a reference for the identification of new drug molecules for the treatment of IPF.
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Descoberta de Drogas , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Fibrose Pulmonar Idiopática , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Animais , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Humanos , Relação Estrutura-Atividade , Camundongos , Estrutura Molecular , Bleomicina , Relação Dose-Resposta a Droga , Camundongos Endogâmicos C57BL , Masculino , Pirróis/química , Pirróis/farmacologia , Pirróis/síntese químicaRESUMO
Dielectric elastomers, such as thermoplastic polyurethanes (TPUs), are widely used as the dielectric layer, encapsulation layer, and substrate of flexible and stretchable devices. To construct capacitors and actuators that work stably upon deformation, it has become urgent to investigate the evolution of dielectricity under stress and strain. However, the lack of effective methods for estimating the dielectric constant of elastomers under strain poses a big challenge. This study reports a device for the in situ measurement of the dielectric constant of TPU under strain. It is found that upon stretching TPU to a strain of 400%, its dielectric constant decreases from 8.02 ± 0.01 to 2.88 ± 0.25 (at 1 MHz). In addition, combined Fourier-transform infrared spectroscopy, the X-ray scattering technique, and atomic force microscopy were utilized to characterize the evolution of the microstructure under strain. The investigation under tensile strain reveals a decreased density and average size of polarized hard domains, along with a tendency of the molecular chains to align in parallel with the tensile stress. The evolution of the microstructures results in a reduction in the measured dielectric constant in TPU.
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Emerging fields, such as wearable electronics, digital healthcare, the Internet of Things, and humanoid robots, highlight the need for flexible devices capable of recording signals on curved surfaces and soft objects. In particular, flexible magnetosensitive devices garner significant attention owing to their ability to combine the advantages of flexible electronics and magnetoelectronic devices, such as reshaping capability, conformability, contactless sensing, and navigation capability. Several key challenges must be addressed to develop well-functional flexible magnetic devices. These include determining how to make magnetic materials flexible and even elastic, understanding how the physical properties of magnetic films change under external strain and stress, and designing and constructing flexible magnetosensitive devices. In recent years, significant progress is made in addressing these challenges. This study aims to provide a timely and comprehensive overview of the most recent developments in flexible magnetosensitive devices. This includes discussions on the fabrications and mechanical regulations of flexible magnetic materials, the principles and performances of flexible magnetic sensors, and their applications for wearable electronics. In addition, future development trends and challenges in this field are discussed.
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Myeloid cell leukemia 1 (Mcl1), a critical protein that regulates apoptosis, has been considered as a promising target for antitumor drugs. The conventional pharmacophore screening approach has limitations in conformation sampling and data mining. Here, we offered an innovative solution to identify Mcl1 inhibitors with molecular dynamics-refined pharmacophore and machine learning methods. Considering the safety and druggability of FDA-approved drugs, virtual screening of the database was performed to discover Mcl1 inhibitors, and the hit was subsequently validated via TR-FRET, cytotoxicity, and flow cytometry assays. To reveal the binding characteristics shared by the hit and a typical Mcl1 selective inhibitor, we employed quantum mechanics and molecular mechanics (QM/MM) calculations, umbrella sampling, and metadynamics in this work. The combined studies suggested that fluvastatin had promising cell inhibitory potency and was suitable for further investigation. We believe that this research will shed light on the discovery of novel Mcl1 inhibitors that can be used as a supplemental treatment against leukemia and provide a possible method to improve the accuracy of drug repurposing with limited computational resources while balancing the costs of experimentation well.
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Antineoplásicos , Reposicionamento de Medicamentos , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Teoria Quântica , Linhagem Celular Tumoral , Fluvastatina/farmacologia , Fluvastatina/química , FarmacóforoRESUMO
The expression of phosphodiesterase 7A (PDE7A) and phosphodiesterase 8A (PDE8) genes is integral to human signaling pathways, and the inhibition of PDE7A has been associated with the onset of various diseases, including effects on the immune system and nervous system. The development of PDE7 selective inhibitors can promote research on immune and nervous system diseases, such as multiple sclerosis, chronic inflammation, and autoimmune responses. PDE8A is expressed alongside PDE8B, and its inhibitory mechanism is still unclear. Studying the mechanisms of selective inhibitors against different PDE subtypes is crucial to prevent potential side effects, such as nausea and cardiac toxicity, and the sequence similarity of the two protein subtypes was 55.9%. Therefore, it is necessary to investigate the differences of both subtypes' ligand binding sites. Selective inhibitors of two proteins were chosen to summarize the reason for their selectivity through molecular docking, molecular dynamics simulation, alanine scanning mutagenesis, and MM-GBSA calculation. We found that Phe384PDE7A, Leu401PDE7A, Gln413PDE7A, Tyr419PDE7A, and Phe416PDE7A in the active site positively contribute to the selectivity towards PDE7A. Additionally, Asn729PDE8A, Phe767PDE8A, Gln778PDE8A, and Phe781PDE8A positively contribute to the selectivity towards PDE8A.
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Inibidores de Fosfodiesterase , Humanos , Inibidores de Fosfodiesterase/farmacologia , Simulação de Acoplamento MolecularRESUMO
The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.
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Antibacterianos , DNA Girase , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , DNA Girase/metabolismo , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/síntese química , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Relação Dose-Resposta a Droga , Camundongos , Células Hep G2 , Simulação de Acoplamento Molecular , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/químicaRESUMO
Arctigenin, a natural product with diverse pharmacological activities, can inhibit cell proliferation and survival and has shown promising potential in cancer research. In this study, we designed a series of arctigenin derivatives with HDAC inhibitory activity based on the synergistic effects between HDAC inhibitors and arctigenin. Among them, compound B7 exhibited significantly higher antiproliferative activity in the MV411 cell line compared to the positive control, tucidinostat. Additionally, enzymatic activity testing was performed with compound B7. Further mechanistic studies indicated that compound B7 induced apoptosis through the Caspase-3 pathway in MV411 cells and enhanced histone acetylation levels in the MV411 cell line. These findings highlight the broad potential application of these arctigenin derivatives in cancer therapy.
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Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily. In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for colorectal cancer, and a series of novel CDK9 inhibitors were rationally designed and synthesized based on the structure of AZD5438 (a pan CDKs inhibitor reported by AstraZeneca). A novel selective CDK9 inhibitor named CLZX-205, which possessed significant CDK9 inhibitory activity (IC50 = 2.9 nM) with acceptable pharmacokinetic properties and antitumor efficacy in vitro and in vivo, was developed. Research on the mechanism indicated that CLZX-205 could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression, and these results were validated at the cellular and tumor tissue levels. Currently, CLZX-205 is undergoing further research as a promising candidate for CRC treatment.
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Apoptose , Quinase 9 Dependente de Ciclina , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fosforilação , RNA Polimerase II/metabolismo , Linhagem Celular TumoralRESUMO
Although ß2-agonists are crucial for treatment of chronic respiratory diseases, optimizing ß2-agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of ß2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated ß2 adrenoceptors (ß2-ARs). Screening for the ß2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial ß2-agonist in HEK-293 cells containing endogenous ß2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential ß2 agonist candidate for further study.
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Agonistas de Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 2 , Humanos , Ratos , Animais , Cobaias , Células HEK293 , Agonistas de Receptores Adrenérgicos beta 2/farmacologiaRESUMO
A series of novel echinatin derivatives with 1,3,4-oxadiazole moieties were designed and synthesized. Most of the newly synthesized compounds exhibited moderate antiproliferative activity against the four cancer cell lines. Notably, Compound T4 demonstrated the most potent activity, with IC50 values ranging from 1.71 µM to 8.60 µM against the four cancer cell lines. Cell colony formation and wound healing assays demonstrated that T4 significantly inhibited cell proliferation and inhibited migration. We discovered that T4 exhibited moderate binding affinity with the c-KIT protein through reverse docking. The results were effectively validated through subsequent molecular docking and c-KIT enzyme activity assays. In addition, Western blot analysis revealed that T4 inhibits the phosphorylation of downstream proteins of c-KIT. The results provide valuable inspiration for exploring novel insights into the design of echinatin-related hybrids as well as their potential application as c-KIT inhibitors to enhance the efficacy of candidates.
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Antineoplásicos , Chalconas , Neoplasias , Oxidiazóis , Humanos , Relação Estrutura-Atividade , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Proliferação de Células , Estrutura Molecular , Linhagem Celular Tumoral , Relação Dose-Resposta a DrogaRESUMO
Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.
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Degeneração Macular , Camundongos , Animais , Humanos , Camundongos Endogâmicos ICR , Células Endoteliais da Veia Umbilical Humana , Degeneração Macular/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio VascularRESUMO
Two-dimensional (2D) ferromagnets have attracted widespread attention for promising applications in compact spintronic devices. However, the controlled synthesis of high-quality, large-sized, and ultrathin 2D magnets via facile, economical method remains challenging. Herein, we develop a hydrogen-tailored chemical vapor deposition approach to fabricating 2D Cr5Te8 ferromagnetic nanosheets. Interestingly, the time period of introducing hydrogen was found to be crucial for controlling the lateral size, and a Cr5Te8 single-crystalline nanosheet of lateral size up to â¼360 µm with single-unit-cell thickness has been obtained. These samples exhibit a leading role of domain wall nucleation in governing the magnetization reversal process, providing important references for optimizing the performances of associated devices. The nanosheets also show notable magnetotransport response, including nonmonotonous magnetic-field-dependent magnetoresistance and sizable anomalous Hall resistivity, demonstrating Cr5Te8 as a promising material for constructing high-performance magnetoelectronic devices. This study presents a breakthrough of large-sized CVD-grown 2D magnetic materials, which is indispensable for constructing 2D spintronic devices.
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Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since its initial isolation and identification, numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives. Despite this, there has been a dearth of comprehensive reviews in the past two decades, leading to challenges in subsequent research on OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships (SARs) of OA and its derivatives to provide valuable reference for future investigations into OA.