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Quitosano , Dioxolanos , Doxorrubicina , Quempferoles , Nanopartículas , Doxorrubicina/administración & dosificación , Dioxolanos/farmacología , Dioxolanos/química , Dioxolanos/administración & dosificación , Animales , Quitosano/química , Quempferoles/farmacología , Quempferoles/administración & dosificación , Nanopartículas/química , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/patología , Carcinoma de Ehrlich/metabolismo , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , PiperidonasRESUMEN
Aims: Five series of novel koumine-like compounds were designed, semi-synthesized and systematically evaluated for antitumor activities.Methods: All compounds were evaluated for antiproliferative activity against four human cancer cell lines, including HT-29, HCT-116, HCT-15 and Caco-2.Results: Most compounds exhibited much higher antiproliferation activities (IC50 <10 µM) than koumine. Two selected compounds A4 and C5 showed comparable antitumor effects to 5-FU in vivo, as well as better safety profiles. Further studies suggested that A4 and C5 could arrest HT-29 cell cycle in G2 phase and raise reactive oxygen species level, thus inducing cell apoptosis related to Erk MAPK and NF-κB signaling pathways inhibition.Conclusion: These results will greatly promote the druggability study of these koumine-like compounds.
[Box: see text].
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Antineoplásicos , Apoptosis , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Animales , Ratones , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Dioxolanos/química , Dioxolanos/farmacología , Dioxolanos/síntesis química , Línea Celular Tumoral , Estructura Molecular , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Alcaloides IndólicosRESUMEN
Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating ß-catenin expression, which is a pivotal protein in the Wnt/ß-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/ß-catenin pathway.
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Neoplasias del Colon , Dioxolanos , Óxido Nítrico , Vía de Señalización Wnt , beta Catenina , Dioxolanos/farmacología , Dioxolanos/química , Humanos , Óxido Nítrico/metabolismo , Neoplasias del Colon/tratamiento farmacológico , beta Catenina/metabolismo , Estructura Molecular , Vía de Señalización Wnt/efectos de los fármacos , Células HCT116 , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , PiperidonasRESUMEN
Myristicin (MYR) mainly occurs in nutmeg and belongs to alkoxy-substituted allylbenzenes, a class of potentially toxic natural chemicals. RNA interaction with MYR metabolites in vitro and in vivo has been investigated in order to gain a better understanding of MYR toxicities. We detected two guanosine adducts (GA1 and GA2), two adenosine adducts (AA1 and AA2), and two cytosine adducts (CA1 and CA2) by LC-MS/MS analysis of total RNA extracts from cultured primary mouse hepatocytes and liver tissues of mice after exposure to MYR. An order of nucleoside adductions was found to be GAs > AAs > CAs, and the result of density functional theory calculations was in agreement with that detected by the LC-MS/MS-based approach. In vitro and in vivo studies have shown that MYR was oxidized by cytochrome P450 enzymes to 1'-hydroxyl and 3'-hydroxyl metabolites, which were then sulfated by sulfotransferases (SULTs) to form sulfate esters. The resulting sulfates would react with the nucleosides by SN1 and/or SN2 reactions, resulting in RNA adduction. The modification may alter the biochemical properties of RNA and disrupt RNA functions, perhaps partially contributing to the toxicities of MYR.
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Activación Metabólica , Derivados de Alilbenceno , Sistema Enzimático del Citocromo P-450 , ARN , Sulfotransferasas , Espectrometría de Masas en Tándem , Animales , Ratones , Sulfotransferasas/metabolismo , Sulfotransferasas/genética , Sulfotransferasas/química , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/química , Derivados de Alilbenceno/química , Derivados de Alilbenceno/metabolismo , ARN/metabolismo , ARN/química , Masculino , Hepatocitos/metabolismo , Dioxolanos/metabolismo , Dioxolanos/química , Dioxolanos/toxicidad , Hígado/metabolismo , Hígado/enzimología , Disulfuros/química , Disulfuros/metabolismo , Myristica/química , Myristica/metabolismoRESUMEN
Chemical investigation of n-hexane extract from the marine sponge Leucetta sp. led to the isolation of five new lipids, 1-5, each characterized by a substituted dioxolane core. The structures of 1-5 were established based on the interpretation of NMR and HRESIMS data. To assign the absolute configuration at C-1', model systems consisting of diastereomers at C-2, C-4, and C-1' of the dioxolane core were prepared from a chiral glycerol dimethylacetal. 1H NMR inspection of model compounds revealed that a pair of C-1' epimers, 11a/c and 11b/d, was indistinguishable, restricting structural assignment by direct comparison of NMR data. In addition, the lack of chromophores in the dioxolane core resulted in unreliable ECD results, with Cotton effects appearing below 190 nm. As an alternative, a chiral NMR method using Eu(hfc)3 revealed notable lanthanide-induced shifts, allowing the spectroscopic discrimination of 11a/c and ent-11a/c. Therefore, the absolute configuration of all five new lipids was determined to be 2S, 4S, 1'S by direct comparison with the Eu(hfc)3-induced 1H NMR data.
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Dioxolanos , Lípidos , Poríferos , Animales , Poríferos/química , Estructura Molecular , Estereoisomerismo , Lípidos/química , Dioxolanos/química , Biología Marina , Resonancia Magnética Nuclear Biomolecular , Espectroscopía de Resonancia MagnéticaRESUMEN
Pancreatic cancer cells highly resistance to conventional chemo drugs, resulting low survival rates. The aim of the study was to design and develop dual targeting polymersomes (DTPS) loaded with phyto alkaloid agent i.e., piperlongumine (PL) for effective pancreatic cancer treatment. Here, hyaluronic acid (HA) was functionalized with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPEPEG-NH2), poly(ethylene glycol) bis (amine) (PEG), and phenylboronic acid (PBA) moieties. The designed DTPS could selectively recognize CD44/sialic acid (SA) and deliver PL to MIA PaCa-2 pancreatic cancer cells, facilitated via HA-CD44 and PBA-SA interactions. Drug release and stability results implied sustained PL release profile and pH sensitivity. DTPS could be more efficiently bound with SA than other sugars based on fluorescence spectroscopy. The anticancer efficacy of designed polymersomes was tested with H6C7 normal pancreas cells and SA/CD44-overexpressed MIA PaCa-2 pancreatic cancer cells. DTPS showed both SA and CD44-mediated higher cellular uptake while single-targeted polymersomes showed CD44-mediated cellular uptake. The PL-loaded DTPS efficiently uptake by MIA PaCa-2 cancer cells, causing up to 80 % cell growth inhibition, reduced cell spheroids volume and increased dead cells by 58.3 %. These results indicate that the newly developed DTPS can effectively serve as a pH-responsive drug delivery system for efficient treatment of cancer.
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Ácidos Borónicos , Dioxolanos , Ácido Hialurónico , Neoplasias Pancreáticas , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Dioxolanos/farmacología , Dioxolanos/química , Línea Celular Tumoral , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Liberación de Fármacos , Receptores de Hialuranos/metabolismo , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Polímeros/química , Supervivencia Celular/efectos de los fármacos , PiperidonasRESUMEN
Nitric oxide (NO) is an important gas messenger molecule with a wide range of biological functions. High concentration of NO exerts promising antitumor effects and is regarded as one of the hot spots in cancer research, that have limitations in their direct application due to its gaseous state, short half-life (seconds) and high reactivity. Lysyl oxidase (LOX) is a copper-dependent amine oxidase that is responsible for the covalent bonding between collagen and elastin and promotes tumor cell invasion and metastasis. The overexpression of LOX in triple-negative breast cancer (TNBC) makes it an attractive target for TNBC therapy. Herein, novel NO donor prodrug molecules were designed and synthesized based on the naturally derived piperlongumine (PL) skeleton, which can be selectively activated by LOX to release high concentrations of NO and PL derivatives, both of them play a synergistic role in TNBC therapy. Among them, the compound TM-1 selectively released NO in highly invasive TNBC cells (MDA-MB-231), and TM-1 was also confirmed as a potential TNBC cell line inhibitor with an inhibitory concentration of 2.274 µM. Molecular docking results showed that TM-1 had a strong and selective binding affinity with LOX protein.
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Dioxolanos , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Óxido Nítrico , Proteína-Lisina 6-Oxidasa , Neoplasias de la Mama Triple Negativas , Proteína-Lisina 6-Oxidasa/metabolismo , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Dioxolanos/farmacología , Dioxolanos/química , Línea Celular Tumoral , Óxido Nítrico/metabolismo , Estructura Molecular , Donantes de Óxido Nítrico/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Profármacos/farmacología , Profármacos/química , PiperidonasRESUMEN
ß-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.
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Antivirales , Dioxolanos , Estereoisomerismo , Dioxolanos/química , Dioxolanos/farmacología , Dioxolanos/síntesis química , Antivirales/química , Antivirales/síntesis química , Antivirales/farmacología , Uracilo/análogos & derivados , Uracilo/química , Uracilo/síntesis química , Uracilo/farmacología , Estructura Molecular , Profármacos/química , Profármacos/farmacología , Profármacos/síntesis químicaRESUMEN
Rigorous risk assessments for those exposed to pesticides are carried out to satisfy crop protection regulatory requirements. Non-dietary risk assessments involve estimating the amount of residue which can be transferred from plant foliage to the skin or clothes, known as dislodgeable foliar residues (DFRs). DFR data are less available than crop residue data as studies are costly and limited by seasonality. European regulatory authorities are reticent to allow extrapolation of study data to different scenarios as the contributory factors have hitherto been poorly identified. This study is the first to use a new laboratory DFR method to investigate how one such factor, pesticide formulation, may affect DFR on a variety of crops. The study used the active substance difenoconazole as both an emulsifiable concentrate (EC 10%) and a wettable powder (WP 10%) with and without adjuvants (Tween 20 and organophosphate tris(2-ethylhexyl)phosphate TEHP) on tomato, French bean and oilseed rape. A comparable DFR% was retained from the WP and EC formulation on most crops except for tomato, where lower DFR% was retained in the case of WP (39 ± 4.7%) compared to EC (60 ± 1.2%). No significant effect of adjuvant addition was observed for either formulation except when mixing TEHP (0.1% w/v) to the EC 10% on French bean, resulting in 8% DFR reduction compared to the EC formulation alone. This research demonstrates the value of a unique DFR laboratory technique in investigating the importance of the formulation and in-tank adjuvants as factors that affect DFR.
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Dioxolanos , Fungicidas Industriales , Residuos de Plaguicidas , Triazoles , Dioxolanos/química , Triazoles/química , Triazoles/análisis , Residuos de Plaguicidas/análisis , Fungicidas Industriales/química , Hojas de la Planta/química , Productos Agrícolas/química , Solanum lycopersicum/química , Contaminación de Alimentos/análisisRESUMEN
Piperlongumine(PL), a natural alkaloid extracted from Piperis Longi Fructus, has attracted much attention in recent years because of its strong anti-tumor activity, little toxicity to normal cells, and excellent sensitizing effect combined with chemotherapy and radiotherapy, which endow PL with unique advantages as an anti-tumor drug. However, similar to other alkaloids, PL has low water solubility and poor bioavailability. To improve the application of PL in the clinical treatment of tumors, researchers have constructed various nano-drug delivery systems to increase the efficiency of PL delivery. This paper reviewed the physicochemical properties, anti-tumor mechanism, combined therapies, and nano-drug delivery systems of PL in recent years. The review aimed to provide a reference for further research on the anti-tumor effect and nano-drug delivery system of PL. Moreover, this review is expected to provide a reference for the development and application of PL in the anti-tumor therapies.
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Dioxolanos , Neoplasias , Dioxolanos/química , Humanos , Animales , Neoplasias/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/administración & dosificación , Sistema de Administración de Fármacos con Nanopartículas/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , PiperidonasRESUMEN
The enantioselective environmental behavior of difenoconazole, a widely utilized triazole fungicide commonly detected in agricultural soils, has yet to be comprehensively explored within the earthworm-soil system. To address this research gap, we investigated the bioaccumulation and elimination kinetics, degradation pathways, biotransformation mechanisms, spatial distribution, and toxicity of chiral difenoconazole. The four stereoisomers of difenoconazole were baseline separated and analyzed using SFC-MS/MS. Pronounced enantioselectivity was observed during the uptake phase, with earthworms exhibiting a preference for (2R,4R)-difenoconazole and (2R,4S)-difenoconazole. A total of five transformation products (TPs) were detected and identified using UHPLC-QTOF/MS in the earthworm-soil system. Four of the TPs were detected in both earthworm and soil, and one TP was produced only in eaerthwroms. Hydrolysis and hydroxylation were the primary transformation pathways of difenoconazole in both earthworms and soil. Furthermore, a chiral TP, 3-chloro, 4-hydroxy difenoconazole, was generated with significant enantioselectivity, and molecular docking results indicate the greater catalytic bioactivity of (2R,4R)- and (2R,4S)-difenoconazole, leading to the preferential formation of their corresponding hydroxylated TPs. Furthermore, Mass Spectrometry Imaging (MSI) was applied for the first time to explore the spatial distribution of difenoconazole and the TPs in earthworms, and the "secretory zone" was found to be the dominant region to uptake and biodegrade difenoconazole. ECOSAR predictions highlighted the potentially hazardous impact of most difenoconazole TPs on aquatic ecosystems. These findings are important for understanding the environmental fate of difenoconazole, evaluating environmental risks, and offering valuable insights for guiding scientific bioremediation efforts.
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Biotransformación , Dioxolanos , Fungicidas Industriales , Oligoquetos , Contaminantes del Suelo , Triazoles , Oligoquetos/metabolismo , Triazoles/metabolismo , Triazoles/química , Fungicidas Industriales/metabolismo , Fungicidas Industriales/química , Animales , Dioxolanos/metabolismo , Dioxolanos/química , Contaminantes del Suelo/metabolismo , Estereoisomerismo , Suelo/química , Espectrometría de Masas en Tándem , Biodegradación AmbientalRESUMEN
Piperlongumine, or piplartine (PL), is a bioactive alkaloid isolated from Piper longum L. and a potent phytoconstituent in Indian Ayurveda and traditional Chinese medicine with a lot of therapeutic benefits. Apart from all of its biological activities, it demonstrates multimodal anticancer activity by targeting various cancer-associated pathways and being less toxic to normal cells. According to their structure-activity relationship (SAR), the trimethylphenyl ring (cinnamoyl core) and 5,6-dihydropyridin-2-(1H)-one (piperdine core) are responsible for the potent anticancer activity. However, it has poor intrinsic properties (low aqueous solubility, poor bioavailability, etc.). As a result, pharmaceutical researchers have been trying to optimise or modify the structure of PL to improve the drug-likeness profiles. The present review selected 26 eligible research articles on PL derivatives published between 2012 and 2023, followed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) format. We have thoroughly summarised the anticancer potency, mode of action, SAR and drug chemistry of the proposed PL-derivatives against different cancer cells. Overall, SAR analyses with respect to anticancer potency and drug-ability revealed that substitution of methoxy to hydroxyl, attachment of ligustrazine and 4-hydroxycoumarin heterocyclic rings in place of phenyl rings, and attachment of heterocyclic rings like indole at the C7-C8 olefin position in native PL can help to improve anticancer activity, aqueous solubility, cell permeability, and bioavailability, making them potential leads. Hopefully, the large-scale collection and critical drug-chemistry analyses will be helpful to pharmaceutical and academic researchers in developing potential, less-toxic and cost-effective PL-derivatives that can be used against different cancers.
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Antineoplásicos Fitogénicos , Dioxolanos , Neoplasias , Dioxolanos/farmacología , Dioxolanos/química , Dioxolanos/síntesis química , Humanos , Relación Estructura-Actividad , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/síntesis química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Animales , Estructura Molecular , PiperidonasRESUMEN
Piperlonguminine (PLG) is a major alkaloid found in Piper longum fruits. It has been shown to possess a variety of biological activities, including anti-tumor, anti-hyperlipidemic, anti-renal fibrosis and anti-inflammatory properties. Previous studies have reported that PLG inhibits various CYP450 enzymes. The main objective of this study was to identify reactive metabolites of PLG in vitro and assess its ability to inhibit CYP450. In rat and human liver microsomal incubation systems exposed to PLG, two oxidized metabolites (M1 and M2) were detected. Additionally, in microsomes where N-acetylcysteine was used as a trapping agent, N-acetylcysteine conjugates (M3, M4, M5 and M6) of four isomeric O-quinone-derived reactive metabolites were found. The formation of metabolites was dependent on NADPH. Inhibition and recombinant CYP450 enzyme incubation experiments showed that CYP3A4 was the primary enzyme responsible for the metabolic activation of PLG. This study characterized the O-dealkylated metabolite (M1) through chemical synthesis. The IC50 shift assay showed time-dependent inhibition of CYP3A4, 2C9, 2E1, 2C8 and 2D6 by PLG. This research contributes to the understanding of PLG-induced enzyme inhibition and bioactivation.
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Activación Metabólica , Citocromo P-450 CYP3A , Dioxolanos , Microsomas Hepáticos , Animales , Humanos , Citocromo P-450 CYP3A/metabolismo , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Ratas , Dioxolanos/farmacología , Dioxolanos/química , Inhibidores del Citocromo P-450 CYP3A/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Masculino , Piperidonas , BenzodioxolesRESUMEN
Most combinations of chemo- and biocatalysis take place in aqueous media or require a solvent change with complex intermediate processing. Using enzymes in the same organic solvent as the chemocatalyst eliminates this need. Here, it was shown that a complete chemoenzymatic cascade to form dioxolanes could be carried out in a purely organic environment. The result, including downstream processing, was compared with a classical mode, shifting solvent. First, a two-step enzyme cascade starting from aliphatic aldehydes to chiral diols (3,4-hexanediol and 4,5-octanediol) was run either in an aqueous buffer or in the potentially biobased solvent cyclopentyl methyl ether. Subsequently, a ruthenium molecular catalyst enabled the conversion to dioxolanes [e. g., (4S,5S)-dipropyl-1,3-dioxolane]. Importantly, the total synthesis of this product was not only highly stereoselective but also based on the combination of biomass, CO2 , and hydrogen, thus providing an important example of a bio-hybrid chemical.
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Dioxolanos , Solventes/química , Dioxolanos/química , Estereoisomerismo , Biocatálisis , Catálisis , Agua/químicaRESUMEN
In an effort to discover anticancer agents with simultaneous effects on tubulin and angiogenesis, we designed and synthesized two series of piperlongumie (PL) derivatives by replacing of phenyl group with a variety of benzoheterocycle (series II) or cyclizing the C7-C8 olefin into an aromatic heterocycle (series I). Most of the new compounds showed better antiproliferative activities against six cancer cell lines than the parent drug PL. Compound II-14b had the best cytotoxic profile of these two series in cancer cells, whilst being relatively low cytotoxicity against normal human cells and high potency against drug-resistant cells. It disrupted cellular microtubule networks and inhibited tubulin assembly with an IC50 value of 5.8 µM. Further studies elucidated that II-14b showed antitumor activities through multiple mechanisms, including the pruduction of abundant ROS, the dissipation of mitochondrial membrane potential, the accumulation of DNA double-strand breaks, and the induction of cell cycle in G2/M phase. More importantly, we have observed that it possesses potential anti-angiogenesis capabilities, including suppression of HUVECs cell migration, invasion, and endothelial tube formation in vitro and in vivo. In vivo assessment indicated that II-14b inhibits the growth and metastasis of MGC-803 xenograft tumour in zebrafish. These findings show that II-14b is a high-efficacy and non-toxic antitumor agent.
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Antineoplásicos , Dioxolanos , Tubulina (Proteína) , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Microtúbulos , Polimerizacion , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/metabolismo , Pez Cebra , Dioxolanos/química , Dioxolanos/farmacologíaRESUMEN
The effects of spraying and root irrigation on the uptake and transport of the fungicide difenoconazole under hydroponic and soil cultivation were investigated. Rice was used as the crop for a short-term exposure experiment. A modified QuEChERS pre-treatment combined with ultra-high-performance liquid chromatography-tandem mass spectrometry was used to extract and detect difenoconazole from rice plants, water and soil. The recoveries of difenoconazole were in the range of 72.8-110.5%, with a relative standard deviation of 2.4-19.5% for all the samples when spiked with 0.01, 0.1 and 1 mg kg-1 of difenoconazole, respectively. The limit of quantitation (LOQ) of this method was 0.01 mg kg-1. The exposure results showed that difenoconazole could be absorbed by rice plants and transmitted to different parts of rice plants in all the treatments. In the hydroponic experiment, difenoconazole was mainly distributed in the roots of rice regardless of whether irrigation or spraying was used. For rice cultivated in soil, difenoconazole mainly accumulated in leaves after the root irrigation treatment, whereas after the spraying treatment, the rice roots were the main site of accumulation of difenoconazole. This experiment extends our knowledge of the influence of the cultivation system and application mode on the translocation of difenoconazole in rice plants.
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Dioxolanos , Oryza , Contaminantes del Suelo , Dioxolanos/análisis , Dioxolanos/química , Oryza/química , Suelo/química , Contaminantes del Suelo/análisis , Triazoles/análisisRESUMEN
Many phytopathogenic fungi can easily infect crops, resulting in crop yield reductions. In continuation of our efforts to develop natural product (NP)-based antifungal agents, a series of N-phenylpyrazole sarisan hybrids 6a-v were prepared via I2 -mediated oxidative cyclization, and their structures were determined by various spectral analyses including IR, 1 H-NMR and ESI-MS. Among all N-phenylpyrazole sarisan hybrids, compounds 6a, 6b, 6e, 6i, 6j and 6r exhibited more encouraging antifungal action against at least two phytopathogenic fungi than the reference fungicide hymexazol. Especially, 6a displayed really encouraging and broad-spectrum antifungal activity against F.â graminearum, V.â mali, and F.â oxysporum f.sp.niveum with the EC50 values of 12.6±0.9, 18.5±0.2, and 37.4±1.8 µg/mL, respectively. Moreover, the structure-activity relationships (SARs) were also observed. Additionally, compounds 6a and 6e also exhibited relative low toxicity on normal LO2 cells. This study indicates that these N-phenylpyrazole sarisan hybrids would shed light on developing novel NP-based antifungal agents.
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Antifúngicos/síntesis química , Productos Biológicos/química , Dioxolanos/química , Antifúngicos/química , Antifúngicos/farmacología , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclización , Evaluación Preclínica de Medicamentos , Fusarium/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Oxidación-Reducción , Pirazoles/química , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1-3 and 1-6, in which γ-butyrolactam replaced α,ß-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1-3 and 1-6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1-3 or 1-6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1-3 and 1-6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.
Asunto(s)
Colitis/tratamiento farmacológico , Dioxolanos/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Animales , Células Cultivadas , Colitis/inducido químicamente , Colitis/metabolismo , Sulfato de Dextran , Dioxolanos/síntesis química , Dioxolanos/química , Relación Dosis-Respuesta a Droga , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
The natural products piperlongumine (1) and ligustrazine (2) have been reported to exert antiproliferative effects against various types of cancer cells by up-regulating the level of reactive oxidative species (ROS). However, the moderate activities of 1 and 2 limit their application. To improve their potential antitumor activity, novel piperlongumine/ligustrazine derivatives were designed and prepared, and their potential pharmacological effects were determined in vitro and in vivo. Among the derivatives obtained, 11 exerted more prominent inhibitory activities against proliferation of drug-sensitive/-resistant cancer cells with lower IC50 values than 1. Particularly, the IC50 value of 11 against drug-resistant Bel-7402/5-FU cells was 0.9 µM, which was about 9-fold better than that of 1 (IC50 value of 8.4 µM). Mechanistic studies showed that 11 demonstrated thioredoxin reductase (TrxR) inhibitory activity, increase of ROS levels, decrease of mitochondrial transmembrane potential levels, and occurrence of DNA damage and autophagy, in a dose-dependent manner, via regulation of DNA damage protein H2AX and autophagy-associated proteins LC3, beclin-1, and p62 in drug-resistant Bel-7402/5-FU cells. Finally, compound 11 at 5 mg/kg displayed potent antitumor activity in vivo with tumor suppression of 76% (w/w). Taken together, compound 11 may represent a promising candidate drug for the chemotherapy of drug-resistant hepatocellular carcinoma and warrant more intensive study.