RESUMEN
Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1a) and of five benzofuran derivatives (2a, 2b, 2c, 2f and 2g) by single crystal X-Ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2b, 2e, and 2g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition > 60%). Compound 2e showed an IC50 of 0.2 µM and was selected for further analysis, results reinforce its anticancer potential.
RESUMEN
The fruit of Choerospondias axillaris (Anacardiaceae), known as south wild jujube in China, has been consumed widely in several regions of the world to produce fruit pastille and leathers, juice, jam, and candy. A comprehensive chemical study on the fresh fruits led to the isolation and identification of 18 compounds, including 7 new (1-7) and 11 known (8-18) comprised of 5 alkenyl (cyclohexenols and cyclohexenones) derivatives (1-5), 3 benzofuran derivatives (6-8), 6 flavonoids (9-14) and 4 lignans (15-18). Their structures were elucidated by extensive spectroscopic analysis. The known lignans 15-18 were isolated from the genus Choerospondias for the first time. Most of the isolates exhibited significant inhibitory activity on α-glucosidase with IC50 values from 2.26 ± 0.06 to 43.9 ± 0.96 µM. Molecular docking experiments strongly supported the potent α-glucosidase inhibitory activity. The results indicated that C. axillaris fruits could be an excellent source of functional foods that acquire potential hypoglycemic bioactive components.
RESUMEN
The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 µM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5-32.8 µM) than the positive control galantamine (IC50 35.3 µM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 µM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.
Asunto(s)
Acetilcolinesterasa , Benzofuranos , Butirilcolinesterasa , Simulación del Acoplamiento Molecular , Benzofuranos/farmacología , Corteza CerebralRESUMEN
Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1-BF7 and benzofuran-1,2,4-triazole compounds BF8-BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1-BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1-BF7 showed lesser binding affinities (-12.63 to -14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8-BF15 (-14.11 to -16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (-16.09 Kcal/mol), BF-12 (-15.75 Kcal/mol), and BF-13 (-15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors' standard reference drug Nesbuvir (-15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme-compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8-BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug.
RESUMEN
NF-κB and MAPK are classic inflammation signaling pathways which regulate inflammation signal transmission and induce the expression of many inflammatory factors. Based on the potent anti-inflammatory activity of benzofuran and its derivatives, several new heterocyclic/benzofuran hybrids were first designed and synthesized by molecular hybridization. Their structure was confirmed by 1H NMR, 13C NMR, HRMS or X-single crystal diffraction. The anti-inflammatory activity of these new compounds was screened by compounds; compound 5d exhibited an excellent inhibitory effect on the generation of NO (IC50 = 52.23 ± 0.97 µM), and low cytotoxicity (IC50 > 80 µM) against the RAW-264.7 cell lines. To further elucidate the possible anti-inflammatory mechanisms of compound 5d, the hallmark protein expressions of the NF-κB and MAPK pathways were studied in LPS-stimulated RAW264.7 cells. The results indicate that compound 5d not only significantly inhibits the phosphorylation levels of IKKα/IKKß, IKßα, P65, ERK, JNK and P38 in the classic MAPK/NF-κB signaling pathway in a dose-dependent manner, but also down-regulates the secretion of pro-inflammatory factors such as NO, COX-2, TNF-α and IL-6. Further, the in vivo anti-inflammatory activity of compound 5d indicated that it could regulate the involvement of neutrophils, leukocytes and lymphocytes in inflammation processes, and reduce the expression of IL-1ß, TNF-α and IL-6 in serum and tissues. These results strongly suggest that the piperazine/benzofuran hybrid 5d has a good potential for developing an anti-inflammatory lead compound, and the anti-inflammatory mechanism might be related to the NF-κB and MAPK signaling pathways.
Asunto(s)
Antiinflamatorios , Benzofuranos , Sistema de Señalización de MAP Quinasas , FN-kappa B , Animales , Ratones , Antiinflamatorios/química , Antiinflamatorios/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Inflamación/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacologíaRESUMEN
Toxoplasmosis, caused by Toxoplasma gondii, affects about 20-30% of the human population every year globally. The emergence of severe side effects of current chemotherapeutics and drug-resistant strains emphasize upon finding new therapeutics to treat toxoplasmosis. Chorismate synthase (CS) is a vital enzyme of shikimate pathway and responsible for formation of chorismate, which acts as a precursor for production of several aromatic compounds important for virulence and survival in many bacteria and protozoans. In this study, comparative modeling was employed to predict the three-dimensional structure of T. gondii chorismate synthase (TgCS) followed by its refinement and validation using various computational tools. The modeled structure of TgCS monomer shows all the conserved features of CS, particularly the beta-alpha-beta sandwich fold. Molecular docking studies has displayed that 5-enolpyruvylshikimate-3-phosphate (EPSP, substrate) and flavin mononucleotide (FMN, cofactor) bind into the active site of TgCS and all the structures (apo, binary, and ternary) were observed to be stable during molecular dynamics (MD) simulation. Subsequently, structure-based virtual screening using TgCS has inferred two of each benzofuran and EPSP analogs as the best hits on the basis of RCS, molecular interactions, ADME properties, and MD simulations. The MD data of resultant protein-ligand complex structures was subjected to calculate the binding energy through MMPBSA method, which highlights that the EPSP analogs have higher binding affinity for the substrate-binding site of TgCS in comparison to benzofuran derivatives as well as substrate. Altogether, our study could pave the way for designing and development of next generation chemotherapeutic molecules against toxoplasmosis.
Asunto(s)
Benzofuranos , Toxoplasma , Toxoplasmosis , Mononucleótido de Flavina/química , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Liasas de Fósforo-Oxígeno , Ácido Shikímico/química , Ácido Shikímico/metabolismo , Toxoplasma/metabolismoRESUMEN
Chemotherapy is one of the most commonly used methods of cancer disease treatment. Due to the acquisition of drug resistance and the possibility of cancer recurrence, there is an urgent need to search for new molecules that would be more effective in destroying cancer cells. In this study, 1-(benzofuran-2-yl)ethan-1-one oxime and 26 oxime ethers containing heterocyclic, alicyclic or aromatic moiety were screened for their cytotoxicity against HeLa cancer cell line. The most promising derivatives with potential antitumor activity were 2-(cyclohexylideneaminoxy)acetic acid (18) and (E)-acetophenone O-2-morpholinoethyl oxime (22), which reduced the viability of HeLa cells below 20% of control at concentrations of 100-250 µg/mL. Some oxime ethers, namely thiazole and benzothiophene derivatives (24-27), also reduced HeLa cell viability at similar concentrations but with lower efficiency. Further cytotoxicity evaluation confirmed the specific toxicity of (E)-acetophenone O-2-morpholinoethyl oxime (22) against A-549, Caco-2, and HeLa cancer cells, with an EC50 around 7 µg/mL (30 µM). The most potent and specific compound was (E)-1-(benzothiophene-2-yl)ethanone O-4-methoxybenzyl oxime (27), which was selective for Caco-2 (with EC50 116 µg/mL) and HeLa (with EC50 28 µg/mL) cells. Considering the bioavailability parameters, the tested derivatives meet the criteria for good absorption and permeation. The presented results allow us to conclude that oxime ethers deserve more scientific attention and further research on their chemotherapeutic activity.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Éteres/química , Oximas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Análisis Espectral , Relación Estructura-ActividadRESUMEN
Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC50 = 0.065 µM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC50 values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 µM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 µM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.
Asunto(s)
Antineoplásicos/farmacología , Benzofuranos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzofuranos/síntesis química , Benzofuranos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Histona Demetilasas/metabolismo , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Relación Estructura-ActividadRESUMEN
Three new benzofuran derivatives, namely ribisin E (1) ribisin F (2) along with ribisin G (3) were isolated from the MeOH extract of the fruiting bodies of Phellinus ribis. Their structures were elucidated based on the NMR analysis. Furthermore, the absolute configuration of ribisin E (1) and ribisin G (3) were deduced by the CD calculations, and the absolute configuration of ribisin F (2) was determined by comparing its CD spectrum and specific rotation with the data of known analogues. All compounds (1-3) exhibited the activity of promoting neurite outgrowth in nerve growth factor (NGF)-ediated PC 12 cell at concentrations ranging from 1 to 30 µM.
Asunto(s)
Benzofuranos , Factor de Crecimiento Nervioso , Animales , Benzofuranos/farmacología , Neuritas , Células PC12 , Phellinus , RatasRESUMEN
The repurposing or repositioning of previously-approved drugs has become an accepted strategy for the expansion of the pharmacopeia for neglected diseases. Accordingly, amiodarone, an inexpensive and extensively- used class III antiarrhythmic has been proposed as a treatment for Chagas' disease and leishmaniasis. Amiodarone has a potent trypanocidal and leishmanicidal action, mainly acting through the disruption of parasite intracellular Ca2+ homeostasis, which is a recognized target of different drugs that have activity against trypanosomatids. Amiodarone collapses the mitochondrial electrochemical potential (Δφm) and induces the rapid alkalinization of parasite acidocalcisomes, driving a large increase in the intracellular Ca2+ concentration. Amiodarone also inhibits oxidosqualene cyclase activity, a key enzyme in the ergosterol synthesis pathway that is essential for trypanosomatid survival. In combination, these three effects lead to parasite death. Dronedarone, a drug synthesized to minimize some of the adverse effects of amiodarone, displays trypanocidal and leishmanicidal activity through the same mechanisms, but curiously, being more potent on Leishmaniasis than its predecessor. In vitro studies suggest that other recently-synthesized benzofuran derivatives can act through the same mechanisms, and produce similar effects on different trypanosomatid species. Recently, the combination of amiodarone and itraconazole has been used successfully to treat 121 dogs naturally-infected by T. cruzi, strongly supporting the potential therapeutic use of this combination against human trypanosomatid infections.
Asunto(s)
Amiodarona , Enfermedad de Chagas , Leishmaniasis , Tripanocidas , Trypanosoma cruzi , Amiodarona/farmacología , Amiodarona/uso terapéutico , Animales , Calcio , Enfermedad de Chagas/tratamiento farmacológico , Perros , Leishmaniasis/tratamiento farmacológicoRESUMEN
Amyloid-ß (Aß) aggregated forms are highly associated with the onset of Alzheimer's disease (AD). Aß abnormally accumulates in the brain and induces neuronal damages and symptoms of AD such as cognitive impairment and memory loss. Since an antibody drug, aducanumab, reduces Aß aggregates and delays clinical decline, clearance of accumulated Aß in the brain is accounted as a therapeutic approach to treat AD. In this study, we synthesized 17 benzofuran derivatives that may disaggregate Aß oligomers and plaques into inert monomers. By a series of Aß aggregation inhibition and aggregates' disaggregation assays utilizing thioflavin T assays and gel electrophoresis, YB-9, 2-((5-methoxy-3-(4-methoxyphenyl)benzofuran-6-yl)oxy)acetic acid, was selected as the final Aß-disaggregator candidate. When it was orally administered to the 8-month-old male transgenic mouse model with five familial AD mutations (5XFAD) via drinking water daily for two months, Aß oligomers and plaques in hippocampus were reduced. Consequently, decreased astrogliosis and rescued synaptic dysfunction were observed in the hippocampus of YB-9-treated 5XFAD mice compared with the untreated transgenic control group.
Asunto(s)
Enfermedad de Alzheimer , Benzofuranos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Transgénicos , Placa AmiloideRESUMEN
A docking study of a novel series of benzofuran derivatives with ERα was conducted. In this study, we report the synthesis of a novel series of benzofuran derivatives and evaluation of their anticancer activity in vitro against MCF-7 human breast cancer cells, as well as their potential toxicity to ER-independent MDA-MB-231 breast cancer cells, human renal epithelial HEK-293 cells, and human immortal keratinocytes (HaCaT cells) by using the MTT colorimetric assay. The screening results indicated that the target compounds exhibited anti-breast cancer activity. The target compound 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy]benzofuran hydrochloride (4e) exhibited excellent activity against anti-oestrogen receptor-dependent breast cancer cells and low toxicity. The preliminary structure-activity relationships of the target benzofuran derivatives have been summarised. In conclusion, the novel benzofuran scaffold may be a promising lead for the development of potential oestrogen receptor inhibitors.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Neoplasias de la Mama/patología , Diseño de Fármacos , Receptores de Estrógenos/metabolismo , Antineoplásicos/síntesis química , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Simulación del Acoplamiento Molecular , Análisis Espectral/métodos , Relación Estructura-ActividadRESUMEN
Bioorganic asymmetric reduction of carbonyl compounds is one of the most important fundamental and practical reactions for producing chiral alcohols. The stereoselective bioreduction of prochiral ketones of benzofuran derivatives in the presence of yeast-like fungus Aureobasidium pullulans contained in the antifungal Boni Protect agent was studied. Biotransformations were carried out under moderate conditions in an aqueous and two-phase system and without multiplication of the bioreagent. Despite similar chemical structure, each of the used ketone has been reduced with varying efficiency and selectivity. One of the reasons for these results is the presence of a whole set of oxidoreductases in A. pullulans cells that are sensitive to the smallest changes in the structure of prochiral substrate. The unsymmetrical methyl ketones were biotransformed with the highest selectivity. Aureobasidium pullulans microorganism is less effective in the reduction of unsymmetrical halomethyl ketones. The presence of a heteroatom in the alkyl group significantly decreases the selectivity of the process. Finally, as a result of the preferred hydride ion transfer from the dihydropyridine ring of the cofactor to the carbonyl double bond on the re side, secondary alcohols of the S and R configuration were obtained with moderate to high enantioselectivity (55-99%).
Asunto(s)
Ascomicetos/metabolismo , Benzofuranos/química , Antifúngicos , Benzofuranos/metabolismo , Agentes de Control Biológico/química , Agentes de Control Biológico/metabolismo , Catálisis , Cetonas/química , Cetonas/metabolismo , Estructura Molecular , Solventes , EstereoisomerismoRESUMEN
A series of fourteen methoxy substituted 2-benzoyl-1-benzofuran derivatives were synthesised and their affinities determined for adenosine A1 and A2A receptors via radioligand binding assays to establish the structure activity relationships pertinent for A1 and A2A affinity. Compound 3j (6,7-dimethoxybenzofuran-2-yl)(3-methoxyphenyl)methanone exhibited A1 affinity (A1Ki (rat) = 6.880 µM) as well as A2A affinity (A2AKi (rat) = 0.5161 µM). Compounds 3a-b &3i-k exhibited selective affinity towards A1 with Ki values below 10 µM. The results indicate that C6,7-diOCH3 substitution on ring A in combination with meta (C3')-OCH3 substitution on ring B is beneficial for A1 and A2A affinity and activity. Compounds 3a-b &3j-k showed low cytotoxicity. Upon in vitro and in silico evaluation, compound 3j may be considered lead-like (i.e. a molecular entity suitable for optimization) and, thus, of value in the design of novel, potent and selective adenosine A1 and A2A receptor antagonists.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Benzofuranos/farmacología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Antagonistas del Receptor de Adenosina A1/síntesis química , Antagonistas del Receptor de Adenosina A1/química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/química , Benzofuranos/síntesis química , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC50â¯=â¯52.0⯱â¯0.09⯵g/ml), 4h (IC50â¯=â¯56.0⯱â¯0.71⯵g/ml) and 4l (IC50â¯=â¯59.3⯱â¯0.55⯵g/ml) were shown significant antileishmanial when compared with standard sodium stibogluconate (IC50â¯=â¯490.0⯱â¯1.5⯵g/ml). Antioxidant study revealed that compounds 4i (IC50â¯=â¯2.44⯱â¯0.47⯵g/ml) and 4l (IC50â¯=â¯3.69⯱â¯0.44⯵g/ml) have shown potent comparable activity when compared with standard ascorbic acid (IC50â¯=â¯3.31⯱â¯0.34⯵g/ml). Molecular docking study was carried out which replicating results of biological activity in case of initial hits 4f and 4h suggesting that these compounds have a potential to become lead molecules in drug discovery process. In silico ADME study was performed for predicting pharmacokinetic profile of the synthesised antileishmanial agents and expressed good oral drug like behaviour.
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Antioxidantes/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Benzofuranos/farmacología , Compuestos de Bencilideno/farmacología , Leishmania donovani/efectos de los fármacos , Microondas , Antioxidantes/síntesis química , Antioxidantes/química , Antiprotozoarios/química , Benzofuranos/química , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/química , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Leishmania donovani/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common type of pancreatic cancer, and has still been the medicinal mystery. New drugs and treatment strategies are urgently needed. In this study, 32 benzofuran derivatives are designed, synthesized and evaluated as potential agents against the pancreatic cancer. Among them, compound 9o with the best physicochemical and pharmacokinetic properties exhibited excellent cytotoxicity against many tumor cell lines. In vivo study showed that compound 9o dramatically suppressed the tumor growth of nude mice. Furthermore, compound 9o could affect the hypoxia environment through Hif-1α/VEGF pathway, resulting in the anti-angiogenic activity. These studies indicated that compound 9o was a promising candidate for the treatment of PDAC, deserving further studies.
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Antineoplásicos/farmacología , Benzofuranos/farmacología , Diseño de Fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Hipoxia/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzofuranos/síntesis química , Benzofuranos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Neoplasias PancreáticasRESUMEN
Tissue-nonspecific alkaline phosphatase (TNAP) by hydrolyzing pyrophosphate, an inhibitor of apatite formation, promotes extracellular matrix calcification during bone formation and growth, as well as during ectopic calcification under pathological conditions. TNAP is a target for the treatment of soft tissue pathological ossification. We synthesized a series of benzofuran derivatives. Among these, SMA14, displayed TNAP activity better than levamisole. SMA14 was found to be not toxic at doses of up to 40µM in osteoblast-like Saos-2 cells and primary osteoblasts. As probed by Alizarin Red staining, this compound inhibited mineral formation in murine primary osteoblast and in osteoblast-like Saos-2 cells.
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Fosfatasa Alcalina/antagonistas & inhibidores , Benzofuranos/síntesis química , Benzofuranos/farmacología , Osteoclastos/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Benzofuranos/efectos adversos , Benzofuranos/química , Calcificación Fisiológica/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Osteoclastos/metabolismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
@#To discover the novel compounds with biological activity, N-hetercycle substituted derivatives were synthesized based on the structure of benzofuran. A series of novel N-hetercycle substituted benzofuran derivatives(2a-2j)were synthesized by the reaction of 2-(4′-florobenzoyl)benzofuran with N-heterocyclic compounds. And the structures were characterized by 1H NMR, 13C NMR and HRMS. Their anti-tumor activities were studied in vitro against a panel of human tumor cell lines(HeLa, A549 and H1975)by the MTT assay. The results indicate that compounds 2a, 2f and 2j are the most potent within this series of compounds against human tumor cell lines, showing that they are promising lead compounds for further structural modifications and biological evaluation.
RESUMEN
Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, Ki=0.07nM; MT2, Ki=0.08nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50=0.8nM and Emax=98%) and 6b (EC50=0.2nM and Emax=121%) exhibited good pharmacological profiles.
Asunto(s)
Benzofuranos/química , Melatonina/análogos & derivados , Amidas/química , Animales , Benzofuranos/síntesis química , Benzofuranos/metabolismo , Células CHO/efectos de los fármacos , Técnicas de Química Sintética , Cricetulus , Células HEK293/efectos de los fármacos , Humanos , Ligandos , Melatonina/agonistas , Melatonina/metabolismo , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/metabolismo , Relación Estructura-ActividadRESUMEN
This study describes the organic synthesis of 5-(2-amimo-4-styryl pyrimidine-4-yl)-4-methoxy benzofuran-6-ol (SPBF) as an example of a benzofuran derivative used as a new series of amyloid imaging agents. These benzofuran derivatives may be useful amyloid imaging agents for detecting B-amyloid plagues in the brain of Alzheimer's disease. The precursor is 1-[6-hydroxy-4-methoxybenzofuran-5-yl]-phenyl butadiene ketone, which react with guanidine hydrochloride. The purification process was done via crystallization using solvent ethanol. The overall yield was 75% and the structure of the synthesized compound was confirmed by correct analytical and spectral data. Also, The synthesized compound was labeled with radioactive iodine -125 via electrophilic substitution reaction, in the presence of iodogen as an oxidizing agent, the labeling process was carried out at 95°C for 20min. The radiochemical yield was determined by using a thin layer chromatography and the yield was equal to 80%. Preliminary an in-vivo study examined normal mice after intravenous injection through the tail vein and the data showed the labeling compound was quickly cleared from most body organs. The radioiodinated compound showed high brain uptake. The results of this study suggest that radioiodinated (SPBF) may be useful as a brain imaging agents.