ABSTRACT
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.
Subject(s)
Activation, Metabolic , Allylbenzene Derivatives , Cytochrome P-450 Enzyme System , RNA , Sulfotransferases , Tandem Mass Spectrometry , Animals , Mice , Sulfotransferases/metabolism , Sulfotransferases/genetics , Sulfotransferases/chemistry , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/chemistry , Allylbenzene Derivatives/chemistry , Allylbenzene Derivatives/metabolism , RNA/metabolism , RNA/chemistry , Male , Hepatocytes/metabolism , Dioxolanes/metabolism , Dioxolanes/chemistry , Dioxolanes/toxicity , Liver/metabolism , Liver/enzymology , Disulfides/chemistry , Disulfides/metabolism , Myristica/chemistry , Myristica/metabolismABSTRACT
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.
Subject(s)
Dioxolanes , Lipids , Porifera , Animals , Porifera/chemistry , Molecular Structure , Stereoisomerism , Lipids/chemistry , Dioxolanes/chemistry , Marine Biology , Nuclear Magnetic Resonance, Biomolecular , Magnetic Resonance SpectroscopyABSTRACT
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.
Subject(s)
Boronic Acids , Dioxolanes , Hyaluronic Acid , Pancreatic Neoplasms , Humans , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Dioxolanes/pharmacology , Dioxolanes/chemistry , Cell Line, Tumor , Boronic Acids/chemistry , Boronic Acids/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Drug Liberation , Hyaluronan Receptors/metabolism , Drug Carriers/chemistry , Drug Delivery Systems , Polymers/chemistry , Cell Survival/drug effects , PiperidonesABSTRACT
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.
Subject(s)
Colonic Neoplasms , Dioxolanes , Nitric Oxide , Wnt Signaling Pathway , beta Catenin , Dioxolanes/pharmacology , Dioxolanes/chemistry , Humans , Nitric Oxide/metabolism , Colonic Neoplasms/drug therapy , beta Catenin/metabolism , Molecular Structure , Wnt Signaling Pathway/drug effects , HCT116 Cells , Apoptosis/drug effects , Reactive Oxygen Species/metabolism , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , PiperidonesABSTRACT
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.
Subject(s)
Dioxolanes , Fungicides, Industrial , Pesticide Residues , Triazoles , Dioxolanes/chemistry , Triazoles/chemistry , Triazoles/analysis , Pesticide Residues/analysis , Fungicides, Industrial/chemistry , Plant Leaves/chemistry , Crops, Agricultural/chemistry , Solanum lycopersicum/chemistry , Food Contamination/analysisABSTRACT
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.
Subject(s)
Dioxolanes , Drug Design , Molecular Docking Simulation , Nitric Oxide , Protein-Lysine 6-Oxidase , Triple Negative Breast Neoplasms , Protein-Lysine 6-Oxidase/metabolism , Humans , Triple Negative Breast Neoplasms/drug therapy , Dioxolanes/pharmacology , Dioxolanes/chemistry , Cell Line, Tumor , Nitric Oxide/metabolism , Molecular Structure , Nitric Oxide Donors/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Prodrugs/pharmacology , Prodrugs/chemistry , PiperidonesABSTRACT
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.
Subject(s)
Antiviral Agents , Dioxolanes , Stereoisomerism , Dioxolanes/chemistry , Dioxolanes/pharmacology , Dioxolanes/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Uracil/analogs & derivatives , Uracil/chemistry , Uracil/chemical synthesis , Uracil/pharmacology , Molecular Structure , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/chemical synthesisABSTRACT
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.
Subject(s)
Dioxolanes , Neoplasms , Dioxolanes/chemistry , Humans , Animals , Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Delivery Systems , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/administration & dosage , Nanoparticle Drug Delivery System/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacology , PiperidonesABSTRACT
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.
Subject(s)
Biotransformation , Dioxolanes , Fungicides, Industrial , Oligochaeta , Soil Pollutants , Triazoles , Oligochaeta/metabolism , Triazoles/metabolism , Triazoles/chemistry , Fungicides, Industrial/metabolism , Fungicides, Industrial/chemistry , Animals , Dioxolanes/metabolism , Dioxolanes/chemistry , Soil Pollutants/metabolism , Stereoisomerism , Soil/chemistry , Tandem Mass Spectrometry , Biodegradation, EnvironmentalABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic , Dioxolanes , Neoplasms , Dioxolanes/pharmacology , Dioxolanes/chemistry , Dioxolanes/chemical synthesis , Humans , Structure-Activity Relationship , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Neoplasms/drug therapy , Neoplasms/pathology , Animals , Molecular Structure , PiperidonesABSTRACT
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.
Subject(s)
Activation, Metabolic , Cytochrome P-450 CYP3A , Dioxolanes , Microsomes, Liver , Animals , Humans , Cytochrome P-450 CYP3A/metabolism , Microsomes, Liver/metabolism , Microsomes, Liver/drug effects , Rats , Dioxolanes/pharmacology , Dioxolanes/chemistry , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Male , Piperidones , BenzodioxolesABSTRACT
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.
Subject(s)
Dioxolanes , Solvents/chemistry , Dioxolanes/chemistry , Stereoisomerism , Biocatalysis , Catalysis , Water/chemistryABSTRACT
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.
Subject(s)
Antineoplastic Agents , Dioxolanes , Tubulin , Animals , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/metabolism , Apoptosis , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Microtubules , Polymerization , Tubulin/metabolism , Tubulin Modulators/pharmacology , Tubulin Modulators/metabolism , Zebrafish , Dioxolanes/chemistry , Dioxolanes/pharmacologyABSTRACT
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.
Subject(s)
Dioxolanes , Oryza , Soil Pollutants , Dioxolanes/analysis , Dioxolanes/chemistry , Oryza/chemistry , Soil/chemistry , Soil Pollutants/analysis , Triazoles/analysisABSTRACT
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.
Subject(s)
Antifungal Agents/chemical synthesis , Biological Products/chemistry , Dioxolanes/chemistry , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Biological Products/chemical synthesis , Biological Products/pharmacology , Cell Line , Cell Survival/drug effects , Cyclization , Drug Evaluation, Preclinical , Fusarium/drug effects , Humans , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Conformation , Oxidation-Reduction , Pyrazoles/chemistry , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Colitis/drug therapy , Dioxolanes/pharmacology , Disease Models, Animal , Inflammation/drug therapy , Macrophages/drug effects , Animals , Cells, Cultured , Colitis/chemically induced , Colitis/metabolism , Dextran Sulfate , Dioxolanes/chemical synthesis , Dioxolanes/chemistry , Dose-Response Relationship, Drug , Inflammation/chemically induced , Inflammation/metabolism , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Male , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Dioxolanes/pharmacology , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/pharmacology , Liver Neoplasms/drug therapy , Pyrazines/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Carcinoma, Hepatocellular/pathology , Dioxolanes/chemistry , Humans , Liver Neoplasms/pathology , Pyrazines/chemistryABSTRACT
Thrombotic diseases seriously threaten human life. Justicia, as a common Chinese medicine, is usually used for anti-inflammatory treatment, and further studies have found that it has an inhibitory effect on platelet aggregation. Therefore, it can be inferred that Justicia can be used as a therapeutic drug for thrombosis. This work aims to reveal the pharmacological mechanism of the anti-thrombotic effect of Justicia through network pharmacology combined with wet experimental verification. During the analysis, 461 compound targets were predicted from various databases and 881 thrombus-related targets were collected. Then, herb-compound-target network and protein-protein interaction network of disease and prediction targets were constructed and cluster analysis was applied to further explore the connection between the targets. In addition, Gene Ontology (GO) and pathway (KEGG) enrichment were used to further determine the association between target proteins and diseases. Finally, the expression of hub target proteins of the core component and the anti-thrombotic effect of Justicia's core compounds were verified by experiments. In conclusion, the core bioactive components, especially justicidin D, can reduce thrombosis by regulating F2, MMP9, CXCL12, MET, RAC1, PDE5A, and ABCB1. The combination of network pharmacology and the experimental research strategies proposed in this paper provides a comprehensive method for systematically exploring the therapeutic mechanism of multi-component medicine.
Subject(s)
Dioxolanes/pharmacology , Fibrinolytic Agents/pharmacology , Gene Regulatory Networks , Lignans/pharmacology , Protein Interaction Maps , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Cells, Cultured , Chemokine CXCL12/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Dioxolanes/chemistry , Drug Discovery/methods , Fibrinolytic Agents/chemistry , Humans , Justicia/chemistry , Lignans/chemistry , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Proto-Oncogene Proteins c-met/metabolism , rac1 GTP-Binding Protein/metabolismABSTRACT
One new dioxolanone derivative, guignardianone G (1) and twelve known compounds (2-13) were isolated from the 95 % ethanol extract of the plant endophytic fungus Phyllosticta capitalensis cultured in rice medium. Among these known compounds, isoaltenuene (3), brassicasterol (7), 5,6-epoxyergosterol (8), citreoanthrasteroid A (9), demethylincisterol A (10), and chaxine C (11) were reported from Phyllosticta sp. for the first time. The structure ofâ 1 was elucidated by 1D- and 2D-NMR experiments and HR-ESI-MS data analysis, and its absolute configuration was established through the comprehensive use of the methods of modified Mosher methods, calculations of ECD spectra and optical rotation values. The neuroprotective activity of compounds (1-9, 11-13) were evaluated on PC12 cells damage induced by glutamate, and compoundsâ 9 andâ 12 showed potential neuroprotective activities with half effective concentration (EC50 ) of 24.2 and 33.9â µM, respectively.