RESUMEN

ß-conglycinin (ß-CG) is a prominent storage protein belonging to the globulin family in soybean (Glycine max) seeds. Along with other soybean proteins, it serves as an important source of essential amino acids and high-quality nutrition. However, the digestibility and nutritional value of ß-CG are key factors affecting the nutritional profile of soy-based foods. The heterotrimeric, secondary, and quaternary structures of ß-CG, particularly the spatial arrangement of its α, α', and ß subunits, influence its functional properties. Considering these aspects, ß-CG emerges as a significant protein with diverse applications in the food and health sectors. Therefore, this review explores ß-CG's composition, structure, function, health implications, and industrial uses. Salient discussions are presented on its molecular structure, nutrition, digestibility, allergenicity, and techno-functions including emulsification, solubility, gelling, and structure-function complexities. Overall, the multifaceted potential of ß-CG in the healthcare sector and the food industry is evident.

Asunto(s)

Antígenos de Plantas , Globulinas , Proteínas de Almacenamiento de Semillas , Proteínas de Soja , Globulinas/química , Proteínas de Almacenamiento de Semillas/química , Antígenos de Plantas/química , Proteínas de Soja/química , Relación Estructura-Actividad , Humanos , Glycine max/química , Animales , Valor Nutritivo

RESUMEN

The present study identified the protective effects of garlic oligo/poly-saccharides of different chain lengths against dextran sulfate sodium (DSS)-induced colitis in mice and elucidated the structure-function relationships. The results showed that oral intake of garlic oligo/poly-saccharides decreased disease activity index, reduced colon shortening and spleen enlargement, and ameliorated pathological damage in the mouse colon. The dysregulation of colonic pro/anti-inflammatory cytokines was significantly alleviated, accompanied by up-regulated antioxidant enzymes, blocked TLR4-MyD88-NF-κB signaling pathway, enhanced intestinal barrier integrity, and restored SCFA production. Garlic oligo/poly-saccharides also reversed gut microbiota dysbiosis in colitic mice by expanding beneficial bacteria and suppressing the growth of harmful bacteria. High-molecular-weight polysaccharides exhibited stronger alleviating effects on DSS-induced colitic symptoms in mice than low-molecular-weight oligo/poly-saccharides did, probably due to their greater ability to be fermented in the colon. Taken together, this study demonstrated the anti-inflammatory effects of garlic oligo/poly-saccharides and revealed that high-molecular-weight polysaccharide fractions were more effective in alleviating DSS-induced colitis.

Asunto(s)

Antiinflamatorios , Colitis , Sulfato de Dextran , Fructanos , Ajo , Microbioma Gastrointestinal , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Ajo/química , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Fructanos/farmacología , Fructanos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Relación Estructura-Actividad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Peso Molecular , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

Enterovirus 71 (EV71) is recognized as a major causative agent of hand, foot, and mouth disease (HFMD), posing a significant global public health concern due to its widespread impact and resulting in a major public health issue worldwide. Despite its prevalence, current clinical therapy lacks effective antiviral agents. Fucosylated chondroitin sulfates (FCS) derived from sea cucumber exhibits a range of biological activities including potent antiviral effects. This study provides compelling evidence of the potent antiviral efficacy of FCS against EV71. To further elucidate the impact of structural variations on the anti-EV71 activity, native FCSs with diverse sulfation patterns and a varity of FCS derivatives were prepared and analyzed. Notably, this study presents the detailed structural characterization of FCSs from the sea cucumbers Holothuria scabra Jaege and Holothuria fuscopunctata. Analysis of the structure-activity relationships revealed that molecular weight, sulfated fucose branches, and sulfation pattern were all crucial factors contributing to the potent inhibitory effects of FCS against EV71. Interestingly, molecular weight emerged as the most significant structural determinant of the antiviral potency. These findings suggest the promising potential of utilizing FCS as an innovative EV71 entry inhibitor for the treatment of HFMD.

Asunto(s)

Antivirales , Sulfatos de Condroitina , Enterovirus Humano A , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Antivirales/farmacología , Antivirales/química , Animales , Enterovirus Humano A/efectos de los fármacos , Relación Estructura-Actividad , Humanos , Pepinos de Mar/química , Chlorocebus aethiops , Peso Molecular , Células Vero

RESUMEN

White rice consumption has been regarded as a potential risk factor for non-communicable diseases including obesity and type 2 diabetes. Thus, increasing attention has been paid to develop slowly digested rices with acceptable palatability. As the most abundant component of rice kernels, the fine molecular structure of starch controls not only the texture & aroma, but also the digestion properties of cooked rice. A large number of studies have been conducted to see what molecular structural features control the digestibility and palatability of cooked rice, which further could be connected to starch biosynthesis to enable rices with targeted functionalities to be chosen in non-empirical ways. Nonetheless, little progress has been made because of improper experimental designs. For example, the effects of starch fine molecular structure on cooked rice digestibility and palatability has been rarely studied within one study, resulting to various digestion results. Even for the same sample, it is hard to obtain consistent conclusions and sometimes, the results/coclusions are even controversy. In this review paper, starch fine molecular structural effects on the texture, aroma and starch digestion properties of cooked white rice were summarized followed by a detailed discussion of the relations between the fine molecular structures of amylopectin and amylose to deduce a more general conclusion of starch molecular structure-cooked rice property relations. It is expected that this review paper could provide useful information in terms of how to develop slowly digested rices with acceptable palatability.

Asunto(s)

Culinaria , Digestión , Oryza , Almidón , Oryza/química , Almidón/química , Almidón/metabolismo , Amilopectina/química , Humanos , Amilosa/química , Relación Estructura-Actividad , Estructura Molecular , Gusto

RESUMEN

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

Asunto(s)

Homeostasis , Isoindoles , Pruebas de Sensibilidad Microbiana , Compuestos de Organoselenio , Oxidación-Reducción , Estreptomicina , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Animales , Ratones , Homeostasis/efectos de los fármacos , Estreptomicina/farmacología , Antituberculosos/farmacología , Antituberculosos/química , Mycobacterium marinum/efectos de los fármacos , Azoles/farmacología , Azoles/química , Relación Dosis-Respuesta a Droga , Antibacterianos/farmacología , Antibacterianos/química , Relación Estructura-Actividad , Estructura Molecular , Ratones Endogámicos BALB C

RESUMEN

Controlling the formation and growth of ice is essential to successfully cryopreserve cells, tissues and biologics. Current efforts to identify materials capable of modulating ice growth are guided by iterative changes and human intuition, with a major focus on proteins and polymers. With limited data, the discovery pipeline is constrained by a poor understanding of the mechanisms and the underlying structure-activity relationships. In this work, this barrier is overcome by constructing machine learning models capable of predicting the ice recrystallisation inhibition activity of small molecules. We generate a new dataset via experimental measurements of ice growth, then harness predictive models combining state-of-the-art descriptors with domain-specific features derived from molecular simulations. The models accurately identify potent small molecule ice recrystallisation inhibitors within a commercial compound library. Identified hits can also mitigate cellular damage during transient warming events in cryopreserved red blood cells, demonstrating how data-driven approaches can be used to discover innovative cryoprotectants and enable next-generation cryopreservation solutions for the cold chain.

Asunto(s)

Criopreservación , Crioprotectores , Cristalización , Hielo , Crioprotectores/farmacología , Crioprotectores/química , Humanos , Criopreservación/métodos , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Aprendizaje Automático , Eritrocitos/efectos de los fármacos , Relación Estructura-Actividad , Descubrimiento de Drogas/métodos

RESUMEN

In the final phases of bacterial cell wall synthesis, penicillin-binding proteins (PBPs) catalyze the cross-linking of peptidoglycan. For many decades, effective and non-toxic ß-lactam antibiotics have been successfully used as mimetics of the d-Ala-d-Ala moiety of the natural substrate and employed as irreversible inhibitors of PBPs. In the years following their discovery, the emergence of resistant bacteria led to a decline in their clinical efficacy. Using Staudinger cycloaddition, we synthesized a focused library of novel monocyclic ß-lactams in which different substituents were introduced at the C4 position of the ß-lactam ring, at the C3 amino position, and at the N1 lactam nitrogen. In biochemical assays, the compounds were evaluated for their inhibitory effect on the model enzyme PBP1b from Streptococcus pneumoniae. Upon investigation of the antibacterial activity of the newly prepared compounds against ESKAPE pathogens, some compounds showed moderate inhibition. We also examined their reactivity and selectivity in a biochemical assay with other enzymes that have a catalytic serine in the active site, such as human cholinesterases, where they also showed no inhibitory activity, highlighting their specificity for bacterial targets. These compounds form the basis for further work on new monocyclic ß-lactams with improved antibacterial activity.

Asunto(s)

Antibacterianos , Proteínas de Unión a las Penicilinas , Streptococcus pneumoniae , beta-Lactamas , Proteínas de Unión a las Penicilinas/antagonistas & inhibidores , Proteínas de Unión a las Penicilinas/metabolismo , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , beta-Lactamas/farmacología , beta-Lactamas/síntesis química , beta-Lactamas/química , Relación Estructura-Actividad , Humanos , Pruebas de Sensibilidad Microbiana

RESUMEN

Argonaute proteins (Agos) represent a highly conserved family of proteins prevalent in all domains of life and have been implicated in various biological processes. Based on the domain architecture, Agos can be divided into long Agos and short Agos. While long Agos have been extensively studied over the past two decades, short Agos, found exclusively in prokaryotes, have recently gained attention for their roles in prokaryotic immune defence against mobile genetic elements, such as plasmids and phages. Notable functional and structural studies provide invaluable insights into the underlying molecular mechanisms of representative short Ago systems. Despite the diverse domain arrangements, short Agos generally form heterodimeric complexes with their associated effector proteins, activating the effector's enzymatic activities upon target detection. The activation of effector proteins in the short Ago systems leads to bacterial cell death, a mechanism of sacrificing individuals to protect the community.

Asunto(s)

Proteínas Argonautas , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/química , Bacterias/metabolismo , Bacterias/genética , Relación Estructura-Actividad , Conformación Proteica , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Humanos , Modelos Moleculares

RESUMEN

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Asunto(s)

Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Humanos , Relación Estructura-Actividad , Estructura Molecular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química

RESUMEN

Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.

Asunto(s)

Antraquinonas , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos , Lipasa , Páncreas , Relación Estructura-Actividad , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/síntesis química , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Páncreas/enzimología , Simulación del Acoplamiento Molecular , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química

RESUMEN

Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1H-pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Tiofenos , Quinasas Asociadas a rho , Proteína de Unión al GTP rhoA , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Apoptosis/efectos de los fármacos , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento Molecular

RESUMEN

Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Piridazinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Piridazinas/farmacología , Piridazinas/química , Piridazinas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Animales , Apoptosis/efectos de los fármacos , Ratones , Estructura Molecular , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Femenino , Ratones Desnudos , Ratones Endogámicos BALB C , Línea Celular Tumoral

RESUMEN

Beta-amyloid (Aß), the most pivotal pathological hallmark for Alzheimer's disease (AD) diagnosis and drug evaluation, was recognized by TZ095, a high-affinity fluorescent probe developed by rational molecular design. With a TICT mechanism, TZ095 exhibited remarkable affinity with Aß aggregates (Kd = 81.54 nM for oligomers; Kd = 66.70 nM for fibril) and substantial fluorescence enhancement (F/F0 = 44), enabling real-time monitoring of Aß in live cells and nematodes. Significantly, this work used TZ095 to construct a new protocol that can quickly and conveniently monitor Aß changes at the cellular and nematode levels to evaluate the anti-AD efficacy of candidate compounds, and four reported Aß-lowering drug candidates were administrated for validation. Imaging data demonstrated that TZ095 can visually and quantitatively track the effect of Aß elimination after drug treatment. Furthermore, TZ095 excelled in ex vivo histological staining of 12-month-old APP/PS1 mouse brains, accurately visualizing Aß plaques. Integrating CUBIC technology, TZ095 facilitated whole-brain, 3D imaging of Aß distribution in APP/PS1 mice, enabling high-resolution in situ analysis of Aß plaques. Collectively, these innovative applications of TZ095 offer a promising strategy for rapid, convenient, and real-time monitoring of Aß levels in preclinical therapeutic assessments.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Diseño de Fármacos , Colorantes Fluorescentes , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Humanos , Ratones , Estructura Molecular , Ratones Transgénicos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Relación Estructura-Actividad , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Relación Dosis-Respuesta a Droga , Imagen Óptica

RESUMEN

Enhancing the efficacy of subunit vaccines relies significantly on the utilization of potent adjuvants, particularly those capable of triggering multiple immune pathways. To achieve synergistic immune augmentation by Toll-like receptor 4 agonist (TLR4a) and nucleotide-binding oligomerization-domain-containing protein 2 agonist (NOD2a), in this work, we conjugated RC529 (TLR4a) and MDP (NOD2a) to give RC529-MDP, and evaluated its adjuvanticity for OVA antigen. Compared to the unconjugated RC529+MDP, RC529-MDP remarkably enhanced innate immune responses with 6.8-fold increase in IL-6 cytokine, and promoted the maturation of antigen-presenting cells (APCs), possibly because of the conjugation of multiple agonists ensuring their delivery to the same cell and activation of various signaling pathways within that cell. Furthermore, RC529-MDP improved OVA-specific antibody response, T cells response and the memory T cells ratio relative to the unconjugated mixture. Therefore, covalently conjugating TLR4 agonist and NOD2 agonist was an effective strategy to enhance immune responses, providing the potential to design and develop more effective vaccines.

Asunto(s)

Acetilmuramil-Alanil-Isoglutamina , Adyuvantes Inmunológicos , Proteína Adaptadora de Señalización NOD2 , Receptor Toll-Like 4 , Proteína Adaptadora de Señalización NOD2/agonistas , Proteína Adaptadora de Señalización NOD2/metabolismo , Receptor Toll-Like 4/agonistas , Animales , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Acetilmuramil-Alanil-Isoglutamina/farmacología , Acetilmuramil-Alanil-Isoglutamina/química , Ratones , Ovalbúmina/inmunología , Humanos , Ratones Endogámicos C57BL , Estructura Molecular , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad

RESUMEN

Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Asunto(s)

Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química

RESUMEN

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.

Asunto(s)

Inhibidores de la Angiogénesis , Antineoplásicos , Proliferación Celular , Diterpenos , Diseño de Fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Diterpenos/farmacología , Diterpenos/síntesis química , Diterpenos/química , Transducción de Señal/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Animales , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo

RESUMEN

A series of arylsulfones and heteroarylsulfones have previously been demonstrated to dysregulate the conserved bacterial ClpP protease, causing the unspecific degradation of essential cellular housekeeping proteins and ultimately resulting in cell death. A cocrystal structure of a 2-ß-sulfonylamide analog, ACP1-06, with Escherichia coli ClpP showed that its 2-pyridyl sulfonyl substituent adopts two orientations in the binding site related through a sulfone bond rotation. From this, a new bis-aryl phosphine oxide scaffold, designated as ACP6, was designed based on a "conformation merging" approach of the dual orientation of the ACP1-06 sulfone. One analog, ACP6-12, exhibited over a 10-fold increase in activity over the parent ACP1-06 compound, and a cocrystal X-ray structure with ClpP confirmed its predicted binding conformation. This allowed for a comparative analysis of how different ligand classes bind to the hydrophobic binding site. The study highlights the successful application of structure-based rational design of novel phosphine oxide-based antibiotics.

Asunto(s)

Antibacterianos , Diseño de Fármacos , Endopeptidasa Clp , Escherichia coli , Óxidos , Fosfinas , Fosfinas/química , Fosfinas/farmacología , Endopeptidasa Clp/metabolismo , Endopeptidasa Clp/antagonistas & inhibidores , Endopeptidasa Clp/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Óxidos/química , Escherichia coli/enzimología , Escherichia coli/efectos de los fármacos , Relación Estructura-Actividad , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/antagonistas & inhibidores , Cristalografía por Rayos X , Modelos Moleculares , Sitios de Unión , Estructura Molecular

RESUMEN

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 µM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.

Asunto(s)

Antineoplásicos , Productos Biológicos , Proliferación Celular , Simulación del Acoplamiento Molecular , Naftoquinonas , Piperidinas , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Naftoquinonas/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Animales , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Relación Estructura-Actividad , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Descubrimiento de Drogas , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

A series of new gold(I) and silver(I) N-heterocyclic carbenes bearing a 1-thio-ß-d-glucose tetraacetate moiety was synthesized and chemically characterized. The compounds' stability and solubility in physiological conditions were investigated employing a multitechnique approach. Interaction studies with biologically relevant proteins, such as superoxide dismutase (SOD) and human serum albumin (HSA), were conducted via UV-vis absorption spectroscopy and high-resolution ESI mass spectrometry. The biological activity of the compounds was evaluated in the A2780 and A2780R (cisplatin-resistant) ovarian cancer cell lines and the HSkMC (human skeletal muscle) healthy cell line. Inhibition studies of the selenoenzyme thioredoxin reductase (TrxR) were also carried out. The results highlighted that the gold complexes are more stable in aqueous environment and capable of interaction with SOD and HSA. Moreover, these carbenes strongly inhibited the TrxR activity. In contrast, the silver ones underwent structural alterations in the aqueous medium and showed greater antiproliferative activity.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Oro , Compuestos Heterocíclicos , Metano , Plata , Reductasa de Tiorredoxina-Disulfuro , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Plata/química , Plata/farmacología , Oro/química , Oro/farmacología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Proliferación Celular/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/antagonistas & inhibidores

RESUMEN

Isoxazoline insecticides have shown broad-spectrum insecticidal activity against a variety of insect pests. However, the high toxicity of isoxazoline compounds towards honeybees restricts their application in crop protection. To mitigate this issue, a series of isoxazoline derivatives containing 2-phenyloxazoline were designed and synthesized. Bioassays revealed that several compounds exhibited promising insecticidal activities against Plutella xylostella, with G28 showing particularly excellent insecticidal activity, reflected by an LC50 value of 0.675 mg/L, which is comparable to that of fluxametamide (LC50 = 0.593 mg/L). Furthermore, G28 also exhibited effective insecticidal activity against Solenopsis invicta. Importantly, bee toxicity experiments indicated that G28 had significantly lower acute oral toxicity (LD50 = 2.866 µg/adult) compared to fluxametamide (LD50 = 1.083 µg/adult) and fluralaner (LD50 = 0.022 µg/adult), positioning it as a promising candidate with reduced toxicity to bees. Theoretical simulation further elucidated the reasons for the selective differences in the ability of isoxazoline to achieve higher insecticidal activity while maintaining lower bee toxicity. This research suggests that isoxazoline compounds containing 2-phenyloxazoline group hold potential as new insecticide candidates and offers insights into the development of novel isoxazoline insecticides with both high efficacy and environmental safety.

Asunto(s)

Diseño de Fármacos , Insecticidas , Isoxazoles , Mariposas Nocturnas , Oxazoles , Insecticidas/síntesis química , Insecticidas/química , Insecticidas/farmacología , Insecticidas/toxicidad , Animales , Oxazoles/química , Oxazoles/toxicidad , Isoxazoles/farmacología , Isoxazoles/química , Mariposas Nocturnas/efectos de los fármacos , Abejas/efectos de los fármacos , Relación Estructura-Actividad