RESUMEN
As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-ß (Aß) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aß42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aß42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aß42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aß42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2- and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aß42 by acting on Aß oligomerization and fibrilization. Besides, TJ1 reversed Aß-, H2O2- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aß42 and Aß plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Barrera Hematoencefálica , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Fármacos Neuroprotectores , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Humanos , Ratones , Ratas , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Fragmentos de Péptidos/metabolismo , Células PC12 , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Oximas/farmacología , Oximas/uso terapéutico , Línea Celular Tumoral , MasculinoRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative condition. 5α-epoxyalantolactone (5α-EAL), a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla, has various pharmacological effects. This work supposed to investigate the improved impact of 5α-EAL on cognitive impairment. 5α-EAL inhibited the generation of nitric oxide (NO) in BV-2 cells stimulated with lipopolysaccharide (LPS) with an EC50 of 6.2 µM. 5α-EAL significantly reduced the production of prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α), while also inhibiting the production of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins. The ability of 5α-EAL to penetrate the blood-brain barrier (BBB) was confirmed via a parallel artificial membrane permeation assay. Scopolamine (SCOP)-induced AD mice model was employed to assess the improved impacts of 5α-EAL on cognitive impairment in vivo. After the mice were pretreated with 5α-EAL (10 and 30 mg/kg per day, i.p.) for 21 days, the behavioral experiments indicated that the administration of the 5α-EAL could alleviate the cognitive and memory impairments. 5α-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice. In summary, these findings highlight the beneficial effects of the natural product 5α-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.
RESUMEN
Inhibition of oxidative stress and ferroptosis is currently considered to be a promising therapeutic approach for neurodegenerative diseases. Herpotrichones, a class of compounds derived from insect symbionts, have shown potential for neuroprotective activity with low toxicity. However, the specific mechanisms through which herpotrichones exert their neuroprotective effects remain to be fully elucidated. In this study, the natural [4 + 2] adducts herpotrichone A (He-A) and its new analogues were isolated from the isopod-associated fungus Herpotrichia sp. SF09 and exhibited significantly protective effects in H2O2-, 6-OHDA-, and RSL3-stimulated PC12 cells and LPS-stimulated BV-2 cells. Moreover, He-A was able to relieve ferroptotic cell death in RSL3-stimulated PC12 cells and 6-OHDA-induced zebrafish larvae. Interestingly, He-A can activate antioxidant elements and modulate the SLC7A11 pathway without capturing oxidic free radical and chelating iron. These findings highlight He-A as a novel hit that protects against ferroptosis-like neuronal damage in the treatment of neurodegenerative diseases.
Asunto(s)
Ferroptosis , Fármacos Neuroprotectores , Estrés Oxidativo , Pez Cebra , Animales , Ferroptosis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Ratas , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Isópodos/efectos de los fármacos , Isópodos/química , Humanos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratones , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Larva/efectos de los fármacos , Larva/crecimiento & desarrolloRESUMEN
Colorectal cancer (CRC) is the third most common type of cancer in the world. It is characterized by complex crosstalk between various signaling pathways, as a result of which it is highly challenging to identify optimal therapeutic targets and design treatment strategies. In this study, we tested the effect of 700 compounds on the CRC cell line HT-29 by using the sulforhodamine B assay and screened out 17 compounds that exhibited high toxicity (indicated by an inhibition rate of ≥75â¯% when applied at a concentration of 10⯵M) against the HT-29 cell line. Next, we investigated the mechanisms underlying the effects of these 17 highly toxic compounds. The results of ferroptosis analysis and electron microscopy showed that compounds 575 and 578 were able to significantly reverse RSL3-induced increase in ferroptosis, while compound 580 had a less pronounced ferroptosis-regulating effect. In subsequent experiments, western blotting showed that compounds 575, 578, and 580, which belong to a class of meroterpene-like compounds that affect ferroptosis, do not induce autophagy or apoptosis in the CRC cell line. Instead, Fe2+ chelation experiments showed that these three compounds can serve as iron chelators by chelating Fe2+ at a 1:1 (chelator: Fe2+) ratio. Specifically, the aldehyde and hydroxyl groups of the benzene ring in these compounds may chelate Fe2+, thus reducing Fe2+ levels in cells and inhibiting ferroptosis. These results indicate that these novel meroterpene-like compounds are potential therapeutic small-molecule candidates for targeting ferroptosis in tumors.
Asunto(s)
Ferroptosis , Quelantes del Hierro , Hierro , Ferroptosis/efectos de los fármacos , Humanos , Quelantes del Hierro/farmacología , Quelantes del Hierro/química , Células HT29 , Hierro/metabolismo , Terpenos/farmacología , Terpenos/química , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Apoptosis/efectos de los fármacosRESUMEN
Inubritantrimer A (1), a trace trimerized sesquiterpenoid [4 + 2] adduct featuring an unusual exo-exo type spiro-polycyclic scaffold, together with three new endo-exo [4 + 2] adducts, inubritantrimers B-D (2-4), were discovered from the flowers of Inula britannica. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, and ECD approaches. 1 is characterized as a novel exo-exo trimer, synthesized biogenetically from three sesquiterpenoid monomers, featuring a unique linkage of C-11/C-1', C-13/C-3' and C-13'/C-3â³, C-11'/C-1â³ through a two-step exo [4 + 2] cycloaddition process. Compounds 1-4 exhibited modest cytotoxicity against breast cancer cells with IC50 values in the range of 5.84-12.01 µM.
Asunto(s)
Inula , Sesquiterpenos , Inula/química , Estructura Molecular , Espectroscopía de Resonancia Magnética , Sesquiterpenos/farmacología , Sesquiterpenos/químicaRESUMEN
Inubritanolides C and D (1 and 2), two exo sesquiterpenoid [4 + 2] adducts with unprecedented interconverting conformations of twist-chair and chair, together with two previously undescribed endo [4 + 2] dimers (3 and 4) were discovered from Inula britannica flowers. Dimers 1 and 2 have an undescribed carbon skeleton comprising of eudesmanolide and guaianolide units with the linkage mode of C-11/C-1' and C-13/C-3' via a Diels-Alder cycloaddition reaction. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, ECD, and variable-temperature NMR experiments. Dimer 2 displayed a strong inhibitory effect on breast cancer cells by promoting lipid ROS production, showing its potential as ferroptosis inducer.
Asunto(s)
Asteraceae , Ferroptosis , Inula , Sesquiterpenos , Inula/química , Conformación Molecular , Sesquiterpenos/farmacología , Sesquiterpenos/química , Estructura MolecularRESUMEN
A series of novel trienomycin A (TA)-mimetic compounds (5a-p) have been designed, synthesized, and evaluated for their in vitro anti-neuroinflammatory and neuroprotective activities. Among them, compounds 5h, 5n, and 5o exhibits relatively strong NO inhibitory activity in LPS-activated BV-2 cells with the EC50 values of 12.4, 17.3, and 8.9 µM, respectively. Moreover, 5h showed evidently neuroprotective effect against H2O2-induced PC-12 cells without cytotoxicity at 20 µM. Overall, these compounds can provide a better understanding of the structure-activity relationship of TA and furnish research ideas for anti-neuroinflammatory and neuroprotective agents.
Asunto(s)
Peróxido de Hidrógeno , Fármacos Neuroprotectores , Ratas , Animales , Peróxido de Hidrógeno/farmacología , Relación Estructura-Actividad , Células PC12 , Alanina , Fármacos Neuroprotectores/farmacologíaRESUMEN
Covering: up to December 2021Picrotoxane sesquiterpenoids are a special category of natural products known to have a picrotoxane skeleton and are characterised by a highly oxidised cis-hydrindene core, lactone rings, and epoxide functionalities. Ever since the first picrotoxane was isolated from Menispermum cocculus in the early 19th century, these compounds have long attracted the attention of natural product chemists, synthetic chemists, and pharmacologists for their particular structures and powerful biological activities. This review extensively summarizes a total of 132 naturally occurring picrotoxane sesquiterpenoids, taking into account their distributions, structural classifications, chemical and bio-synthetic researches, and bioactivities. It provides a comprehensive and in-depth perspective for further investigation on picrotoxane sesquiterpenoids.
Asunto(s)
Productos Biológicos , Sesquiterpenos , Sesquiterpenos/farmacología , Sesquiterpenos/química , Productos Biológicos/farmacología , Productos Biológicos/química , LactonasRESUMEN
Flowers of Inula britannica commercially serve as pharmaceutical herbs in the manufacturing of medicinal products. In the current study, sesquiterpenoids of I. britannica flowers' extract and their potential effects against triple-negative breast cancer (TNBC) cells were investigated. Eight structurally diverse sesquiterpenoids, including one sesquiterpenoid dimer (1) and seven sesquiterpenoid monomers (2−8) were isolated from this source. The structures of all compounds were elucidated by 1D/2D NMR data, and their absolute configurations were discerned by single crystal X-ray diffraction. All of the compounds were tested for their potential effects against TNBC. Specifically, 5 displayed strong antiproliferative potency against TNBC cells with a high selective index (SI) on MCF-7 cells (SI > 4 of IC50 on MDA-MB-468/IC50 on MCF-7), and dimer 1 (IC50 = 8.82 ± 0.85 µM) showed better antiproliferative potency against MCF-7 cells than the other monomers did (2−8) (IC50 > 20 µM). To our best knowledge, compound 5 is the first sesquiterpenoid targeting TNBC cells.
Asunto(s)
Inula , Sesquiterpenos , Neoplasias de la Mama Triple Negativas , Flores/química , Humanos , Inula/química , Estructura Molecular , Sesquiterpenos/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,6-O,O-diacetylbritannilactone (OABL), a 1,10-seco-eudesmane sesquiterpene lactone isolated from the herb Inula britannica L., exhibited strong anti-inflammatory activity in vitro as well as favorable BBB penetration property. OABL reduced LPS-induced neuroinflammation in BV-2 microglial cells as assessed by effects on the levels of inflammatory mediators including NO, PGE2, TNF-α, iNOS, and COX-2, as well as the translocation of NF-κB. Besides, OABL also exhibited pronounced neuroprotective effects against oxytosis and ferroptosis in the rat pheochromocytoma PC12 cell line. For in vivo research, OABL (20 mg/kg B.W., i.p.) for 21 d attenuated the impairments in cognitive function observed in 6-month-old 5xFAD mice, as assessed with the Morris water maze test. OABL restored neuronal damage and postsynaptic density protein 95 (PSD95) expression in the hippocampus. OABL also significantly reduced the accumulation of amyloid plaques, the Aß expression, the phosphorylation of Tau protein, and the expression of BACE1 in AD mice brain. In addition, OABL attenuated the overactivation of microglia and astrocytes by suppressing the expressions of inflammatory cytokines, and increased glutathione (GSH) and reduced malondialdehyde (MDA) and super oxide dismutase (SOD) levels in the 5xFAD mice brain. In conclusion, these results highlight the beneficial effects of the natural product OABL as a novel treatment with potential application for drug discovery in AD due to its pharmacological profile.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Sesquiterpenos , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas , Cognición , Modelos Animales de Enfermedad , Lactonas/farmacología , Lactonas/uso terapéutico , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Sesquiterpenos/farmacologíaRESUMEN
Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (â¼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinï¬ammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC50 value of 0.57 µM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on H2O2-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 µM, as well as selectively metal chelating properties via chelating Cu2+. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the ï¬rst report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.
Asunto(s)
Acetofenonas/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Fármacos Neuroprotectores/farmacología , Oximas/farmacología , Acetofenonas/síntesis química , Acetofenonas/química , Acetilcolinesterasa/metabolismo , Animales , Compuestos de Bifenilo/antagonistas & inhibidores , Línea Celular , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Electrophorus , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Oximas/síntesis química , Oximas/química , Picratos/antagonistas & inhibidores , Ratas , Relación Estructura-ActividadRESUMEN
Neuroinflammation plays a key etiological role in the progressive neuronal damage of neurodegenerative diseases. Our phenotypic-based screening discovered 1,6-O,O-diacetylbritannilactone (OABL, 1) from Inula britannica exhibited the potential anti-neuroinflammatory activity as well as a favorable blood-brain barrier penetration. 1 and its active derivative Br-OABL (2) with insert of Br at the C-14 position both modulated TLR4/NF-kB/MAPK pathways. However, proteome-wide identification of 1 binding proteins remains unclear. Here, we employed an adapted isoTOP-ABPP, quantitative thiol reactivity profiling (QTRP) approach, to identify and quantify thiol reactivity binding proteins in murine microglia BV-2 cells. We screened out 15 proteins co-targeted by 1 and 2, which are involved in cellular response to oxidative stress and negative regulation NF-κB transcription factor in biological processes. In site-specific profiling, NLRP3 was identified as a covalent target of 1 and 2 for the first time, and the Cys483 of NLRP3 NACHT domain was identified as one active-site of NLRP3 cysteine residues that can be covalently modified by the α-methylene-γ-lactone moiety. Furthermore, NLRP3 was validated to be directly binded by 1 and 2 by cellular thermo shift assay (CETSA) and activity-based protein profiling (ABPP), and NLRP3 functions were also verified by small interfering RNA approach. Notably, OABL treatment (i.p., 20 mg/kg/day) for 21 days reduced inflammation in 5XFAD mice brain. Together, we applied the QTRP to uncover the binding proteins of OABL in BV-2 cells, among which NLRP3 was revealed as a new covalent target of 1 and 2 against neuroinflammation.
Asunto(s)
Inflamación/tratamiento farmacológico , Lactonas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Sesquiterpenos/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/metabolismo , Inula/química , Lactonas/química , Ratones , Estructura Molecular , Proteína con Dominio Pirina 3 de la Familia NLR/análisis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sesquiterpenos/química , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/análisisRESUMEN
Dried flowers of Inula britannica commercially serve as pharmaceutical/nutraceutical herbs in the manufacture of medicinal products and functional tea that has been reported to possess extensive biological property. However, the neuroprotective constituents in I. britannica flowers are not known. In the current study, phytochemicals of sesquiterpenoid-enriched I. britannica flowers extract and their potential multifunctional neuroprotective effects were investigated. Nineteen structurally diverse sesquiterpenoids, including two new sesquiterpenoid dimers, namely, inubritanolides A and B (1, 2), and four new sesquiterpenoid monomers (3-6), namely, 1-O-acetyl-6-O-chloracetylbritannilactone (3), 6-methoxybritannilactone (4), 1-hydroxy-10ß-methoxy-4αH-1,10-secoeudesma-5(6),11(13)-dien-12,8ß-olide (5) and 1-hydroxy-4αH-1,10-secoeudesma-5(6),10(14),11(13)-trien-12,8ß-olide (6), as well as 13 known congeners (7-19) were isolated from this source. The structures of compounds 1-6 were elucidated by 1D- and 2D- NMR and HR-ESI-MS data, and their absolute configurations were discerned by electronic circular dichroism (ECD) data analysis and single crystal X-ray diffraction. Interestingly, inubritannolide A (1) is a new type [4 + 2] Diels-Alder dimer featuring a hepta-membered cycloether skeleton. Most of the compounds showed potential multifunctional neuroprotective effects, including antioxidative, anti-neuroinflammatory, and microglial polarization properties. Specifically, 1 and 6 displayed slight strong neuroprotective potency against different types of neuronal cells mediated by various inducers including H2O2, 6-hydroxydopamine (6-OHDA), and lipopolysaccharide (LPS). Overall, this is the first report on multifunctional neuroprotective effects of sesquiterpenoid-enriched I. britannica flowers extract, which supports its potential pharmaceutical/nutraceutical application in neurodegenerative diseases.
Asunto(s)
Antioxidantes/farmacología , Flores/química , Inula/química , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/tratamiento farmacológico , Estructura Molecular , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Fourteen eremophilane sesquiterpenoids (1-14), including nine new congeners, septoreremophilanes A-I (1-9), together with three known sesquiterpenes (15-17), two known tetralone derivatives (18, 19), and two known cholesterol analogues (20, 21), were isolated from the endophytic fungus Septoria rudbeckiae. Compounds 1-6 and 7a belong to the family of the highly oxygenated eremophilane sesquiterpenoids with a 6/6/5 tricyclic system and bearing a hemiacetal moiety. The inhibitions of all metabolites against eight bacteria were estimated in vitro, and nine new metabolites (1-9) were tested for antineuroinflammatory activity. Notably, the effects of 4 against Pseudomonas syringae pv. actinidae and 20 against Bacillus cereus displayed potent inhibitory, with the MIC values of 6.25 and 6.25 µM, respectively. Further, scanning electron microscopy analyses indicated that 4 and 20 were to change the outer configuration of bacterial cells, respectively, and the investigations demonstrated that 4 and 20 may act as potential structure templates for the development of the agrochemical bactericides. Additionally, compound 6 displayed potent inhibition of NO generation in lipopolysaccharide-induced BV-2 microglial cells (IC50 = 12.0 ± 0.32 µM), and the conceivable anti-inflammatory mechanisms implicated were also investigated by molecular docking. Thus, the bioactive metabolites of the strain S. rudbeckiae may serve as a novel resource to be developed.
Asunto(s)
Ascomicetos , Sesquiterpenos , Antibacterianos/farmacología , Antiinflamatorios/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/farmacologíaRESUMEN
An investigation of the fruiting bodies of edible mushroom Ganoderma lucidum produced 13 steroids, containing one new lanostane-type triterpene compound, named ganoderterpene A (1). Nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data were used to deduce these structures. All the isolates were evaluated for their ability to suppress NO generation in BV-2 microglial cells treated with lipopolysaccharide (LPS) and exhibited moderate to strong inhibition effects, with IC50 values in the range 7.15-36.88 µM. Among the tested compounds, compound 1 exhibited the most marked activity with an IC50 value of 7.15 µM, and the structure-activity relationships were studied. This study showed that compound 1 significantly suppressed the activation of MAPK and TLR-4/NF-κB signaling pathways, as evidenced by an immunofluorescence assay and a molecular docking experiment. Furthermore, compound 1 effectively improved the LPS-induced mitochondrial membrane potential and apoptosis. These findings suggest that ganoderterpene A could exert protective effects in microglial cells from apoptosis by restraining the inflammatory response. Hence, G. lucidum could be used as a novel preventative agent for neurodegenerative disorders.
Asunto(s)
Ganoderma , Reishi , Triterpenos , Apoptosis , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Lipopolisacáridos , Simulación del Acoplamiento Molecular , FN-kappa B/genética , Receptor Toll-Like 4/genética , Triterpenos/farmacologíaRESUMEN
Dysregulation of neuroinflammation is a key pathological factor in the progressive neuronal damage of neurodegenerative diseases. An in-house natural products library of 1407 compounds were screened against neuroinflammation in lipopolysaccharide (LPS)-activated microglia cells to identify a novel hit 1,6-O,O-diacetylbritannilactone (OABL) with anti-neuroinflammatory activity. Furthermore, a 1,10-seco-eudesmane sesquiterpenoid library containing 33 compounds was constructed by semisynthesis of a major component 1-O-acetylbritannilactone (ABL) from the traditional Chinese medicinal herb Inula Britannica L. Compound 15 was identified as a promising anti-neuroinflammatory agent by nitrite oxide (NO) production screening. 15 could attenuate tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) productions, and inhibit the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at a submicromolar level. Mechanistic study revealed that 15 significantly modulated TLR4/NF-kB and p38 MAPK pathways, and upregulated the anti-oxidant response HO-1. Besides, 15 promoted the conversion of the microglia from M1 to M2 phenotype by increasing levels of arginase-1 and IL-10. The structure-activity relationships (SARs) analysis indicated that the α-methylene-γ-lactone motifs, epoxidation of C5=C10 bond and bromination of C14 were important to the activity. Parallel artificial membrane permeation assay (PAMPA) also demonstrated that 15 and OABL can overcome the blood-brain barrier (BBB). In all, compound 15 is a promising anti-neuroinï¬ammatory lead with potent anti-inï¬ammatory effects via the blockage of TLR4/NF-κB/MAPK pathways, favorable BBB penetration property, and low cytotoxicity.
Asunto(s)
Antiinflamatorios/uso terapéutico , FN-kappa B/antagonistas & inhibidores , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Sesquiterpenos de Eudesmano/uso terapéutico , Receptor Toll-Like 4/efectos de los fármacos , Antiinflamatorios/farmacología , Humanos , Modelos Moleculares , Sesquiterpenos de Eudesmano/farmacología , Relación Estructura-ActividadRESUMEN
A series of novel pyrazole-benzimidazole derivatives (6-42) have been designed, synthesized and evaluated for their in vitro antiproliferative activity against the HCT116, MCF-7 and Huh-7 cell lines. Among them, compounds 17, 26 and 35 showed significant antiproliferative activity against HCT116 cell lines with the IC50 values of 4.33, 5.15 and 4.84 µM, respectively. Moreover, fluorescent staining studies showed compound 17 could induce cancer cells apoptosis. The flow cytometry assay revealed that compound 17 could induce cell cycle arrest at G0/G1 phase. All in all, these consequences suggest that pyrazole-benzimidazole derivatives could serve as promising compounds for further research to develop novel and highly potent cancer therapy agents.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Making full use of the undeveloped bioactive natural product derivatives by selectively delivering them to target sites can effectively increase their druggability and reduce the wastage of resources. Azo-based prodrugs are widely regarded as an effective targeted delivery means for colon-related disease treatment. Herein, we report a new-type of azo-based nanoprodrug obtained from bioactive natural products, in which the readily available podophyllotoxin natural products are connected with methoxy polyethylene glycol (mPEG) via a multifunctional azobenzene group. The amphiphilic prodrug can form nanosized micelles in water and will be highly selectively activated by azoreductases, leading to the in situ generation of anticancer podophyllotoxin derivatives (AdP) in the colon after the cleavage of the azo bond. To satisfy the demand of drug carriers for cancer combination therapy in clinics, α-CD is further introduced into this nanoprodrug micelle system to form a supramolecular hydrogel via a cascade self-assembly strategy. Using imaging mass spectrometry (IMS), the colon-specific drug release ability of the hydrogel after oral administration is demonstrated at the molecular level. Finally, the nanoprodrug hydrogel is further used as a carrier to load a hydrophilic anti-cancer drug 5-FU during the hierarchical self-assembly process and to co-deliver AdP and 5-FU for the drug combination. The combination use of AdP and 5-FU provides enhanced cytotoxicity which indicates a significant synergistic interaction. This work offers a new way to enhance the therapeutic effect of nanoprodrugs via drug combination, and provides a new strategy for reusing bioactive natural products and their derivatives.
Asunto(s)
Antineoplásicos/farmacología , Hidrogeles/química , Nanopartículas/química , Podofilotoxina/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Hidrogeles/síntesis química , Micelas , Estructura Molecular , Tamaño de la Partícula , Podofilotoxina/química , Profármacos/síntesis química , Profármacos/química , Células VeroRESUMEN
BACKGROUND AND PURPOSE: Pancreatic cancer is an exceptionally fatal disease. However, therapeutic drugs for pancreatic cancer have presented a serious shortage over the past few decades. Signal transducer and activator of transcription-3 (STAT3) is persistently activated in many human cancers where it promotes tumour development and progression. Natural products serve as an inexhaustible source of anticancer drugs. Here, we identified the natural product trienomycin A (TA), an ansamycin antibiotic, as a potential inhibitor of the STAT3 pathway with potent activity against pancreatic cancer. EXPERIMENTAL APPROACH: Effects of trienomycin A on transcriptional activity of STAT3 were assessed by the STAT3-luciferase (STAT3-luc) reporter system. In vitro and in vivo inhibitory activity of TA against pancreatic cancer made use of molecular docking, surface plasmon resonance (SPR) assay, MTS assay, colony formation assay, transwell migration/invasion assay, flow cytometric analysis, immunofluorescence staining, quantitative real-time polymerase chain reaction (PCR), western blotting, tumour xenograft model, haematoxylin and eosin (H&E) staining and immunohistochemistry. KEY RESULTS: Trienomycin A directly bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, thus inhibiting the STAT3 pathway. Trienomycin A also inhibited colony formation, proliferation, migration and invasion of pancreatic cancer cell lines. Trienomycin A also markedly blocked pancreatic tumour growth in vivo. More importantly, trienomycin A did not show obvious toxicity at the effective dose in mice. CONCLUSIONS AND IMPLICATIONS: Trienomycin A exerted anti-neoplastic activity by suppressing STAT3 activation in pancreatic cancer. This natural product could be a novel therapeutic candidate for pancreatic cancer.
Asunto(s)
Productos Biológicos , Neoplasias Pancreáticas , Alanina/análogos & derivados , Animales , Apoptosis , Productos Biológicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Ratones , Simulación del Acoplamiento Molecular , Neoplasias Pancreáticas/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 µM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.