RESUMO
Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 µM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.
Assuntos
Transdução de Sinais , Estilbenos , Camundongos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Estilbenos/farmacologia , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologiaRESUMO
The aberrant activation of NLRP3 inflammasomes is intricately linked to various inflammatory diseases. In this study, we present the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the pterostilbene skeleton. All compounds underwent screening to evaluate their inhibitory effects on LPS/Nigericin-induced IL-1ß secretion and anti-cellular pyroptosis. Most compounds exhibit good biological activity and cellular safety, with compound D20 showing the most prominent activity. Preliminary mechanism studies suggest that compound D20 may affect the assembly of NLRP3 inflammasomes by targeting the NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasomes. The in vivo anti-inflammatory activity demonstrated significant therapeutic effect of compound D20 on DSS-induced acute colitis model in mice. This work has important reference significance for the development of drugs targeting NLRP3 inflammasomes.
RESUMO
The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1ß production and pyroptosis. The structure-activity relationships was deduced, and finally 1-((E)-4-(2-ethoxyethoxy)styryl)-3,5-dimethoxy-2-((E)-2-nitrovinyl)benzene (D22) was found to be a low-toxic compound with most potent inhibitory efficacy (against IL-1ß: IC50 = 2.41 µM). Preliminary mechanism studies showed that compound D22 may affect the assembly of NLRP3 inflammasome by targeting NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasome. The in vivo anti-inflammatory activity indicated that compound D22 had significant therapeutic effects on DSS-induced mouse acute colitis models.
Assuntos
Colite , Inflamassomos , Estilbenos , Animais , Camundongos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estilbenos/química , Estilbenos/farmacologiaRESUMO
In recent decades, significant progress has been made in liver tissue engineering through the use of 3D bioprinting technology. This technology offers the ability to create personalized biological structures with precise geometric design capabilities. The complex and multifaceted nature of liver diseases underscores the need for advanced technologies to accurately mimic the physiological and mechanical characteristics, as well as organ-level functions, of liver tissue in vitro. Bioprinting stands out as a superior option over traditional two-dimensional cell culture models and animal models due to its stronger biomimetic advantages. Through the use of bioprinting, it is possible to create liver tissue with a level of structural and functional complexity that more closely resembles the real organ, allowing for more accurate disease modeling and drug testing. As a result, it is a promising tool for restoring and replacing damaged tissue and organs in the field of liver tissue engineering and drug research. This article aims to present a comprehensive overview of the progress made in liver tissue engineering using bioprinting technology to provide valuable insights for researchers. The paper provides a detailed account of the history of liver tissue engineering, highlights the current 3D bioprinting methods and bioinks that are widely used, and accentuates the importance of existing in vitro liver tissue models based on 3D bioprinting and their biomedical applications. Additionally, the article explores the challenges faced by 3D bioprinting and predicts future trends in the field. The progress of 3D bioprinting technology is poised to bring new approaches to printing liver tissue in vitro, while offering powerful tools for drug development, testing, liver disease modeling, transplantation, and regeneration, which hold great academic and practical significance.
Assuntos
Bioimpressão , Animais , Impressão Tridimensional , Engenharia Tecidual/métodos , Tecnologia , Fígado , Alicerces TeciduaisRESUMO
A series of novel pathalide-1,2,4-oxadiazole analogs were synthesized for discovering novel anti-inflammatory agents. After the assessment of their cytotoxicity inâ vitro, all compounds had been screened for their anti-inflammatory activity by evaluating their inhibitory effect on LPS-induced NO production in RAW 264.7 macrophages. SARs had been concluded, and finally compound E13 was found to be the most potent compound. This compound could also significantly decrease the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound E13 could inhibit the TLR4/NF-κB and ERK/p38 signaling pathways. These findings indicate that E13 holds great potential to be a lead compound for discovering novel anti-inflammatory drugs.
Assuntos
Benzofuranos , Oxidiazóis , Animais , Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Oxidiazóis/farmacologia , Células RAW 264.7RESUMO
An expedient cyclopropanation of α-methylene-ß-lactams with α-ketoesters mediated by P(NMe2)3 has been developed. This reaction enables rapid access to a series of functionalized spirocyclopropyl ß-lactams in good yields from bench-stable starting materials under mild conditions. The experimental results indicated that the C3-substituent of the α-methylene-ß-lactam not only significantly impacted the reaction efficiency and stereochemistry but also played a pivotal role in determining the chemoselectivity of the reaction.
RESUMO
A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Cromonas/farmacologia , Interleucina-6/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Adjuvante de Freund , Interleucina-6/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Malignant melanomas are amongst the most aggressive cancers. BRAF Inhibitors have exhibited therapeutic effects against BRAF-mutant melanoma. In continuation of our earlier studies on anti-melanoma agents based on 1H-pyrazole skeleton, two sets of novel compounds that include 1H-pyrazole-4-amines FA1 - FA13 and corresponding urea derivatives FN1 - FN13 have been synthesized and evaluated for their BRAFV600E inhibitory and antiproliferation activities. Compound FN10 displayed the most potent biological activity against BRAFV600E (IC50 = 0.066 µm) and the A375 human melanoma cell line (GI50 = 0.81 µm), which was comparable to the positive control vemurafenib, and more potent than our previously reported 1H-pyrazole-3-amines and their urea derivatives. The results of SAR studies and molecular docking can guide further optimization and may help to improve potency of these pyrazole-based anti-melanoma agents.
Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Pirazóis/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Ureia/químicaRESUMO
Twenty-three novel resveratrol-based cinnamic ester hybrids were designed and synthesized. All the compounds were evaluated for their anti-inflammatory activity using RAW264.7 cells. Among them, compound D15 was found to be the most potent one in inhibiting NO production in LPS-stimulated RAW264.7 cells. The further study indicated that compound D15 could suppress expression of proteins iNOS, COX-2, p-p65, and p-IκB LPS-induced. Immunofluorescence further revealed compound D15 could reduce activation p65 in nuclei. All the results indicated that the anti-inflammatory activity of title compound may partly due to its inhibitory effect on the NF-κB signaling pathway.
Assuntos
Cinamatos/síntese química , Cinamatos/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Macrófagos/efeitos dos fármacos , Estilbenos/síntese química , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Western Blotting , Células Cultivadas , Cinamatos/química , Cristalografia por Raios X , Ésteres/química , Macrófagos/imunologia , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Células RAW 264.7 , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Estilbenos/químicaRESUMO
Due to the rising incidence and lack of effective treatments, malignant melanoma is the most dangerous form of skin cancer, so that new treatment strategies are urgently needed. Several recent developments indicate that the V600E mutant BRAF (BRAF(V600E) ) is a validated target for antimelanoma-drug development. Based on in silico screening results, a series of novel pyrazole derivatives has been designed, synthesized, and evaluated in vitro for their inhibitory activities against BRAF(V600E) melanoma cells. Compound 3d exhibited the most potent inhibitory activity with an IC50 value of 0.63â µM for BRAF(V600E) and a GI50 value of 0.61â µM for mutant BRAF-dependent cells. Furthermore, the QSAR modeling and the docking simulation of inhibitor analogs provide important pharmacophore clues for further structural optimization.
Assuntos
Descoberta de Drogas , Melanoma/tratamento farmacológico , Pirazóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Humanos , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Pirazóis/química , Pirazóis/uso terapêutico , Neoplasias Cutâneas/genéticaRESUMO
Due to their structural diversities and prevalent biological activities, natural products (NPs) are momentous resources for drug discovery. Although NPs have a wide range of biological activities, many exhibit structural complexity that leads to synthetic difficulties, which combines with inefficient biological activity, toxicity, and unfavorable pharmacokinetic characteristics and ultimately imparts poor safety and efficacy outcomes. Progress in crystallization and computational techniques allow crystallography to have a seasonable influences on drug discovery. By co-crystallizing with proteins, therapeutic targets of NPs in specific diseases can be identified. By analyzing the co-crystal information, the structure-activity relationships (SARs) of NPs targeting specific proteins can be grasped. Under the guidance of co-crystal information, directional structural modification and simplification are powerful strategies for overcoming limitations of NPs, improving the success rate of NP-based drug discovery, and obtaining NP-based drugs with high selectivity, low toxicity and favorable pharmacokinetic characteristics. Here, we review the co-crystal information of a selection of NPs, focusing on the SARs of NPs reflected by co-crystal information and the modification and simplification strategies of NPs, and discuss how to apply co-crystal information in the optimization of NP-based lead compound.
Assuntos
Produtos Biológicos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Descoberta de Drogas/métodos , Relação Estrutura-Atividade , CristalografiaRESUMO
There are two conformationally similar mol-ecules in the asymmetric unit of he title compound, C18H18O4, in which the dihedral angles between the benzene rings are 23.54â (12) and 31.11â (12)°. In the crystal, C-Hâ¯π inter-actions (minimum Hâ¯ring centroid distance = 2.66â Å) link the mol-ecules into a layered structure extending down a.
RESUMO
BACKGROUND: Inflammation is closely related to the occurrence and development of various diseases in the clinical scope. Finding effective anti-inflammatory agents is of great significance for clinical treatment. A series of novel ferrocenyl(piperazine-1-yl)methanone-based sulfamides and carboxamides were synthesized to discover potent anti-inflammatory agents. METHODS: The compounds were characterized by 1H NMR, 13C NMR, and MS spectra. Compound 5h was further determined by single crystal X-ray diffraction. All the target compounds were screened for anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW264.7 macrophages. The novel compound (4i) is the preliminary anti-inflammatory mechanism detected by western blot. RESULTS: In a multi-stage screening campaign, compound 4i was shortlisted, which exhibited physicochemical properties suitable for human administration. Among them, compound 4i was found to be most potent in inhibiting NO production (IC50 = 7.65 µM) with low toxicity. This compound also exhibited significant inhibition of the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound 4i could inhibit the activation of the LPS-induced TLR4/NF-κB signaling pathway. CONCLUSION: The promising anti-inflammatory activity of compound 4i compared with the reference drug suggests that this compound may contribute as a lead compound in the search for new potential anti-inflammatory agents.
Assuntos
Anti-Inflamatórios , Lipopolissacarídeos , Humanos , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Transdução de Sinais , Piperazinas/farmacologiaRESUMO
A series of resveratrol derivatives possessing curcumin moiety were synthesized and evaluated for their antiproliferative activity against three cancer cell lines including murine melanoma B16-F10, human hepatoma HepG2 and human lung carcinoma A549. Among them, compound C5 displayed the most potent in vitro antiproliferative activity against B16-F10 with IC(50) value of 0.71 µg/mL. Compound C5 also exhibited good tubulin polymerization inhibitory activity with IC(50) value of 1.45 µg/mL. Furthermore, docking simulation was carried out to position C5 into the tubulin-colchicine binding site to determine the probable binding mode.
Assuntos
Curcumina/química , Estilbenos/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Terciária de Proteína , Resveratrol , Estilbenos/síntese química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/químicaRESUMO
Two series of urea and thiourea derivatives (1a-11a, 1b-11b) have been synthesized; all the 22 compounds were reported for the first time. Their anti-proliferative activities against the melanoma cell line B16-F10 were evaluated. Among the compounds tested, compound 6b exhibited the most potent activity in melanoma cells growth inhibition (IC(50) = 0.33 µM). The bioassay tests showed that anti-proliferative activities of these novel compounds were possibly caused by inhibition of ERK1/2 phosphorylation level. Therefore, compound 6b can be a potential anti-melanoma agent and an inhibitor of ERK1/2 phosphorylation deserving further research.
Assuntos
Melanoma Experimental/tratamento farmacológico , Ureia/síntese química , Ureia/farmacologia , Animais , Bioensaio , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases , Espectroscopia de Ressonância Magnética , Melanoma Experimental/patologia , Camundongos , Fosforilação , Espectrometria de Massas por Ionização por Electrospray , Tioureia/síntese química , Tioureia/farmacologia , Tioureia/uso terapêutico , Ureia/uso terapêuticoRESUMO
The oxadiazole core is considered a privileged moiety in many medicinal chemistry applications. The oxadiazole class includes 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, and 1,2,5-oxadiazole. Compounds bearing an oxadiazole ring show a wide range of biological activities, such as anticancer, antibacterial, anti-inflammatory, anti-malarial, and insecticidal properties. Among oxadiazoles, the 1,3,4-oxadiazole has been the most widely explored moiety in medicinal chemistry research. This review is primarily focused on the anticancer, antibacterial, and anti-inflammatory activities of compounds containing 1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,5-oxadiazole reported in the last five years.
Assuntos
Anti-Inflamatórios , Oxidiazóis , Antibacterianos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassay tests show that compound 4a exhibited high activity against human gastric cancer cell SGC-7901, liver cancer Hep-G2 and human prostate PC-3 cell lines with IC(50) values of 21.23±0.99, 29.43±0.32 and 30.89±1.07 µM, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results show that compound 4a can inhibit telomerase with IC(50) value of 4.0±0.32 µM. Docking simulation was performed to position compound 4a into the telomerase (3DU6) active site to determine the probable binding model.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Pirazóis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Telomerase/antagonistas & inibidoresRESUMO
A series of pyridine acyl sulfonamide derivatives (1-24) have been designed and synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among all the compounds, compound 23 displayed the most potent COX-2 inhibitory activity with an IC(50) of 0.8 µM. Antitumor and anti-inflammatory assays indicated that compound 23 owned high antiproliferative activity against B16-F10, HepG2 and MCF-7 cancer cell lines as well as COX-2-derived prostaglandin E(2) (PGE(2)) inhibitory activity of murine macrophage RAW 264.7 cell line with IC(50) values of 2.8, 1.2, 1.8 and 0.15 µM, respectively. Docking simulation was performed to position compound 23 into the COX-2 active site to determine the probable binding model.
Assuntos
Antineoplásicos/química , Inibidores de Ciclo-Oxigenase 2/química , Piridinas/química , Sulfonamidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Melanoma Experimental/tratamento farmacológico , Camundongos , Modelos Moleculares , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Twenty-three resveratrol derivatives possessing chalcone moiety were synthesized and characterized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Compound C19 exhibited the most potent activity in vitro, which inhibited the growth of HepG2, B16-F10, and A549 cell lines with IC(50) values of 0.2, 0.1, and 1.4 µg/mL, respectively. Compound C19 also exhibited significant tubulin polymerization inhibitory activity (IC(50)=2.6 µg/mL). Docking simulation was performed to position compound C19 into the tubulin-colchicine binding site to determine the probable binding mode.
Assuntos
Chalcona/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Moduladores de Tubulina/síntese química , Sítios de Ligação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Ligação Proteica , Resveratrol , Estilbenos/síntese química , Relação Estrutura-AtividadeRESUMO
As nitrogen-containing five-membered heterocyclic structural units, the substituted pyrazole derivatives have a broad spectrum of pharmacological activities, especially 4,5-dihydro-1H-pyrazoles that also commonly known as 2-pyrazolines. Since 2010, considerable studies have been found that the 2-pyrazoline derivatives possess potent anticancer activities. In the present review, it covers the pyrazoline derivatives reported by literature from 2010 till date (2010-2019). This review aims to establish the relationship between the anticancer activities variation and different substituents introduced into a 2-pyrazoline core, which could provide important pharmacophore clues for the discovery of new anticancer agents containing 2-pyrazoline scaffold.