ABSTRACT
BACKGROUND: The formation of amyloid-ß (Aß) plaques is one of the key neuropathological hallmarks of Alzheimer's disease (AD). Near-infrared (NIR) probes show great potential for imaging of Aß plaques in vivo and in vitro. Dicyanoisophorone (DCIP) based Aß probes have attracted considerable attention due to their exceptional properties. However, DCIP probes still has some drawbacks, such as short emission wavelength (<650 nm) and low fluorescence intensity after binding to Aß. It is clear that further modification is needed to improve their luminescence efficiency and sensitivity. RESULTS: We designed and synthesize four novel pyrrolidine-alkylamino-substituted DCIP derivatives (6a-d) as imaging agents for ß-amyloid (Aß) aggregates. Compound 6c responds better to Aß aggregates than the other three compounds (6a, 6b and 6d) and its precursor DCIP. The calculated detection limit is to be as low as 0.23 µM. Compound 6c shows no cytotoxicity in the tested concentration for SH-SY5Y and HL-7702 cells. Additionally, compound 6c is successfully applied to monitor Aß aggregates in live SH-SY5Y cells and APP/PS1 transgenic mice. The retention time in the transgenic mice brain is much longer than that of age-matched wild-type mice. SIGNIFICANCE: The results indicates that compound 6c had an excellent ability to penetrate the blood-brain barrier and it could effectively distinguish APP/PS1 transgenic mice and wide-type mice. This represents its promising applications for Aß detection in basic and biomedical research.
Subject(s)
Cyclohexanones , Humans , Cell Line , Amyloid beta-Protein Precursor/analysis , Amyloid beta-Protein Precursor/chemistry , Amyloid beta-Protein Precursor/metabolism , Pyrrolidines/chemistry , Cyclohexanones/chemical synthesis , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Spectroscopy, Near-Infrared , Molecular Structure , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Spectrometry, Fluorescence , Models, Molecular , Protein Structure, Tertiary , Molecular Docking Simulation , Cell Survival/drug effects , Animals , Mice , Male , Mice, Inbred C57BL , Brain/metabolism , Amination , AlkylationABSTRACT
Mesotrione, as a widely used herbicide, is present in the environment in detectable amounts, causing serious damage. Here, we aimed to investigate the effect of mesotrione on Caco-2 cells and the possibility of its toxicity mitigation by cichoric acid. Therefore, we analyzed the cytotoxicity of both these compounds and the selected oxidative stress parameters, apoptosis and interaction of both the tested compounds with the cell membrane and their accumulation within the cells. In cytotoxicity studies, the stimulating activity of mesotrione was observed, and simultaneously, the inhibitory effect of cichoric acid was noticed. This effect was related to the results of oxidative stress analysis and apoptosis measurements. The activity level of key enzymes (glutathione peroxidase, catalase and superoxide dismutase) in Caco-2 cells exposed to cichoric acid was higher as compared to that of the control. The treatment with mesotrione did not induce apoptosis in the Caco-2 cells. The penetration of the studied compounds into the Caco-2 cells was measured by using an HPLC methodology, and the results indicate mesotrione's high penetration capacity. The distribution of charge on the surface of the cell membranes changed under the influence of both compounds. Considering the mutual interactions of beneficial and potentially toxic food ingredients, it should be noted that, despite the observed favorable trend, cichoric acid is not able to overcome the toxic and cancer-stimulating effects of this pesticide.
Subject(s)
Apoptosis , Caffeic Acids , Cyclohexanones , Oxidative Stress , Humans , Caco-2 Cells , Apoptosis/drug effects , Cyclohexanones/pharmacology , Oxidative Stress/drug effects , Caffeic Acids/pharmacology , Succinates/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma/metabolism , Herbicides/toxicity , Superoxide Dismutase/metabolism , Cell Survival/drug effects , Catalase/metabolism , Glutathione Peroxidase/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolismABSTRACT
Phytochemical investigation on the fruits of Cydonia oblonga Mill., a traditional Uighur medicine, led to the isolation of seven undescribed and nine known megastigmane glycosides. Their structures including absolute configurations were characterized by an extensive analysis of spectroscopic data including HRESIMS and NMR, combined with ECD calculations. Additionally, compounds 1, 2, 4, and 6-16 exhibited anti-inflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6 in RAW264.7 cells induced by lipopolysaccharides (LPS) with inhibitory rates of 10.79%-44.58% at 20 µM.
Subject(s)
Cyclohexanones , Glycosides , Lipopolysaccharides , Norisoprenoids , Norisoprenoids/chemistry , Norisoprenoids/pharmacology , Norisoprenoids/isolation & purification , Mice , Glycosides/chemistry , Glycosides/isolation & purification , Glycosides/pharmacology , RAW 264.7 Cells , Animals , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Cyclohexanones/isolation & purification , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Molecular Structure , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Structure-Activity Relationship , Dose-Response Relationship, Drug , GlucosidesABSTRACT
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Arabidopsis , Drug Design , Enzyme Inhibitors , Herbicides , 4-Hydroxyphenylpyruvate Dioxygenase/antagonists & inhibitors , Arabidopsis/drug effects , Arabidopsis/enzymology , Arabidopsis Proteins/antagonists & inhibitors , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/metabolism , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Cyclohexanones/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Herbicides/chemical synthesis , Herbicides/pharmacology , Ketones/chemical synthesis , Ketones/pharmacology , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Triticum/drug effectsABSTRACT
Tembotrione is a triketone herbicide widely used for broad-spectrum weed control in corn but not registered for use in wheat. A wide collection of spring, winter, and EMS-derived mutant lines of wheat was evaluated for their response to tembotrione treatment. Two winter wheat (WW) genotypes (WW-1 and WW-2) were found to be least sensitive to this herbicide, surviving >6 times the field recommended dose (92 g ai ha-1) compared to the most sensitive genotype (WW-24). Further, HPLC analysis using [14C] tembotrione suggested that both WW-1 and WW-2 metabolized tembotrione rapidly to nontoxic metabolites. Pretreatment with a P450 inhibitor (malathion) followed by tembotrione application increased the sensitivity of WW-1 and WW-2 genotypes to this herbicide, suggesting likely involvement of P450 enzymes in metabolizing tembotrione similar to corn. Overall, our results suggest that the genotypes WW-1 and WW-2 can potentially be used to develop tembotrione-resistant wheat varieties.
Subject(s)
Herbicides , Herbicides/pharmacology , Herbicides/metabolism , Triticum/genetics , Triticum/metabolism , Cyclohexanones/pharmacology , Sulfones/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Zea mays/metabolismABSTRACT
4-hydroxyphenylpyruvate dioxygenase (HPPD) Inhibitor Sensitive 1 (HIS1) is an endogenous gene of rice, conferring broad-spectrum resistance to ß-triketone herbicides. Similar genes, known as HIS1-like genes (HSLs), exhibit analogous functions and can complement the herbicide-resistant characteristics endowed by HIS1. The identification of HIS1 and HSLs represents a valuable asset, as the intentional pairing of herbicides with resistance genes emerges as an effective strategy for crop breeding. Encoded by HIS1 is a Fe(II)/2-oxoglutarate-dependent oxygenase responsible for detoxifying ß-triketone herbicides through hydroxylation. However, the precise structure supporting this function remains unclear. This work, which determined the crystal structure of HIS1, reveals a conserved core motif of Fe(II)/2-oxoglutarate-dependent oxygenase and pinpoints the crucial residue dictating substrate preference between HIS1 and HSL.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Herbicides , Oryza , Oryza/metabolism , 4-Hydroxyphenylpyruvate Dioxygenase/chemistry , 4-Hydroxyphenylpyruvate Dioxygenase/genetics , 4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Ketoglutaric Acids , Oxygenases , Herbicides/pharmacology , Ferrous Compounds , Enzyme Inhibitors/pharmacologyABSTRACT
4-Hydroxyphenylpyruvate dioxygenase inhibitors (Echinochloa crus-galli 1.13.11.27, HPPD) have gained significant popularity as one of the best-selling herbicides worldwide. To identify highly effective HPPD inhibitors, a rational design approach utilizing bioisosterism was employed to create a series of 2-(arylformyl)cyclohexane-1,3-dione derivatives. A total of 29 novel compounds were synthesized and characterized through various techniques, including IR, 1H NMR, 13C NMR, and HRMS. Evaluation of their inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD) revealed that certain derivatives exhibited superior potency compared to mesotrione (IC50 = 0.204 µM). Initial herbicidal activity tests demonstrated that compounds 27 and 28 were comparable to mesotrione in terms of weed control and crop safety, with compound 28 exhibiting enhanced safety in canola crops. Molecular docking analyses indicated that the quinoline rings of compounds 27 and 28 formed more stable π-π interactions with the amino acid residues Phe-360 and Phe-403 in the active cavity of AtHPPD, surpassing the benzene ring of mesotrione. Molecular dynamics simulations and molecular structure comparisons confirmed the robust binding capabilities of compounds 27 and 28 to AtHPPD. This study provides a valuable reference for the development of novel triketone herbicide structures, serving as a blueprint for future advancements in this field.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Arabidopsis , Herbicides , Structure-Activity Relationship , Molecular Docking Simulation , 4-Hydroxyphenylpyruvate Dioxygenase/chemistry , Cyclohexanones/pharmacology , Herbicides/chemistry , Arabidopsis/metabolism , Enzyme Inhibitors/chemistryABSTRACT
One widely known herbicide target is 4-hydroxyphenylpyruvate dioxygenase (HPPD). Avena sativa HPPD is less sensitive to mesotrione (herbicide) than Arabidopsis thaliana HPPD. HPPD inhibitor-sensitivity is governed by the dynamic behavior of the C-terminal α-helix of HPPD (H11) in closed and open forms. However, the specific relationship between the plant inhibitor sensitivity and H11 dynamic behavior remains unclear. Herein, we determined the conformational changes in H11 to understand the inhibitor-sensitivity mechanism based on free-energy calculations using molecular dynamics simulations. The calculated free-energy landscapes revealed that Arabidopsis thaliana HPPD preferred the open form of H11 in the apo form and the closed-like form in complex with mesotrione, whereas Avena sativa HPPD exhibited the opposite tendency. We also identified some important residues involved in the dynamic behavior of H11. Therefore, inhibitor sensitivity is governed by indirect interactions due to the protein flexibility caused by the conformational changes of H11.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Arabidopsis , Dioxygenases , Herbicides , 4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Arabidopsis/metabolism , Cyclohexanones/pharmacology , Herbicides/pharmacology , Herbicides/chemistry , Enzyme Inhibitors/chemistryABSTRACT
The aim of our study was to evaluate the use of Raman spectroscopy for pre-diagnostic estimation of weed response to bleaching herbicides. Model plants were Chenopodium album and Abutilon theophrasti treated with mesotrione (120 g a.i. ha-1). Raman single-point measurements were taken 1, 2, 3, and 7 days after herbicide application from different points on the leaves. Principal component analysis (PCA) was carried out on data normalized by the highest intensity band at 1522 cm-1 and using spectral region from 950 to 1650 cm-1 comprising mainly contributions of carotenoids. The carotenoids by intensive band at â¼1522 cm-1 and bands with lower intensity at â¼1155 and 1007 cm-1 in treated plants were confirmed. According to PC1 (the first principal component) and PC2 (the second principal component), the highest intensity bands responsible for treatment differentiation in C. album could be assigned to chlorophyll, lignin, and carotenes. According to PC1 in A. theophrasti leaves the treatment differences could be observed 7 days after mesotrione treatment and PC2 gave a clear separation between all control and treated leaf samples. Raman spectroscopy may be a good complement to invasive analytical methods, in assessing the plant abiotic stress induced by bleaching herbicides.
Subject(s)
Herbicides , Herbicides/toxicity , Spectrum Analysis, Raman , Cyclohexanones/pharmacology , Carotenoids , Weed ControlABSTRACT
Newly synthesized dehydroxymethyl epoxyquinomycin (DHMEQ) derivatives 6-9, which contain a tertiary hydroxyl group instead of the original secondary hydroxyl group, showed improved solubility in alcohol while maintaining their inhibitory activity against nitric oxide (NO) production, which is used as an indicator of nuclear factor-kappa B (NF-κB) inhibitory activity. We also synthesized a derivative 5 having a cyclopropane ring and a tertiary hydroxyl group and examined its inhibitory activity against NO production. Although it reacted with a nucleophile in a flask, it did not inhibit NO production. The change from a secondary hydroxyl group to a tertiary hydroxyl group contributed to improve the solubility of the compounds while retaining NO inhibitory activity, but had no effect on improving the activity of the cyclopropane form. Compounds in which the secondary hydroxyl group of DHMEQ was converted to a tertiary hydroxyl group would be excellent NF-κB inhibitor candidates because their solubility is improved without decreasing NO inhibitory activity.
Subject(s)
Cyclopropanes , NF-kappa B , Cyclohexanones/pharmacologyABSTRACT
4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD, a Fe(II)/α-ketoglutarate dependent oxygenases), is a popular herbicide target. In this work, two pharmacophore models based on common molecular characteristics (HipHop) and receptor-ligand complex (CBP) were generated for virtual screening for HPPD inhibitors. About 1,000,000 molecules containing diketone structure from PubChem were filtered by Lipinski's rules to build a 3D database. Then the database was screened through combining HipHop model, CBP model, ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction and molecular docking. Subsequently, based on the specific binding mode and affinity of HPPD inhibitors, 4 molecules with high -CDOCKER energy, good aqueous solubility and human safety predicative properties values were screened. From the screening results and combined with previous work, three novel HPPD inhibitors were designed and synthesized through fragment splicing and bioisosterism strategies. Compound IV-a exhibited similar inhibition of Arabidopsis thaliana HPPD (AtHPPD) and herbicidal activity as mesotrione. Crop selectivity showed that compound IV-a had better crop safety than mesotrione. Comparing the molecular properties, ADMET and molecular docking studies indicated that compounds IV-a exhibited better properties than mesotrione, which could be further modified as novel HPPD inhibitor herbicides.
Subject(s)
Arabidopsis , Herbicides , Humans , Structure-Activity Relationship , Molecular Docking Simulation , Cyclohexanones/pharmacology , Herbicides/pharmacology , Herbicides/chemistry , Molecular Structure , Enzyme Inhibitors/pharmacologyABSTRACT
The herbicides not only produce a lethal effect on herbs but also indirectly harm those species which use herbs as host plants during their life cycle. The adverse effect of herbicide is comparatively more than any insecticide found in the agricultural industry. Herbicides act as enzyme inhibitors that block the synthesis of essential biomolecules in herbs. Action mechanisms in which herbicides act on the plant body as well as the classification of the herbicides according to their mode of action have been recorded. Lethal effects of herbicides cause qualitative and quantitative losses of herb-weeds and associated beneficial herbs from crop fields that lead to the decline in diversity of butterfly population. Lack of food sources, alteration of life cycle and morphological anomalies are found as a result of herbicidal interference on enzymatic reactions in butterflies. Beneficial organisms and pollinators are included within the affected ones. We selected the butterfly as it is recognized as a good indicator species. The effects of two graminicide fluazifop-p-butyl and sethoxydim, and a surfactant (like 'Preference' that help to increase penetration) were evaluated on Icaricia icarioides blackmorei and Pieris rapae in the laboratory. Glyphosate and glufosinate ammonium (GLA) kill milkweed plants (Asclepias sp.) by blocking the 5-enolpyruvylshikimate-3 phosphate synthase (EPSPS) enzyme. 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), an herbicide used in forest and nature reserves, is toxic to springtails (Onychiurus quadriocellatus) upon direct contact resulting a disastrous effect on Monarch. Fifth instar caterpillars of skipper butterfly Calpodes ethlius die when they are fed GLA-treated host plants. Atrazine and S-metolachlor are the two other herbicides which are thought to have a role on milkweed plant whose leaves are the food of the larvae. Triclopyr, sethoxydim, and imazapyr are the three herbicides that reduced the adult emergence of Behr's metalmark butterfly. The objective of the study is to provide precise information regarding the relationship between herbicides and butterflies as well as the recommendation of feasible strategies for butterfly conservation with respect to weed management.
Subject(s)
Butterflies , Herbicides , Animals , Butterflies/physiology , Herbicides/toxicity , Cyclohexanones/pharmacology , LarvaABSTRACT
Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of L-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of L-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC-ESI-MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. Moreover, it has been proven that formed NTBC metabolites, such as CHD, cause a decrease in L-tyrosine, L-tryptophan, and L-phenylalanine concentrations by about 34%, 59% and 51%, respectively, compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC-ESI-MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Saccharomyces cerevisiae , Humans , Saccharomyces cerevisiae/metabolism , 4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Tandem Mass Spectrometry , Cyclohexanones/pharmacology , Cyclohexanones/therapeutic use , Nitrobenzoates/metabolism , Metabolome , Tyrosine/metabolismABSTRACT
N-Methyl-D-aspartate receptors (NMDARs) in the brain are influenced by psychoactive drugs such as 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (ketamine) and its analog 2-(ethylamino)-2-(3-methoxyphenyl)-cyclohexanone (methoxetamine). The recreational methoxetamine use can cause several toxicities and methoxetamine-related deaths have also been reported. Therefore, it has been banned in many countries. Since 2020, methoxetamine derivatives, 2-(ethylamino)-2-(m-tolyl)cyclohexan-1-one (deoxymethoxetamine) and 2-(isopropylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxisopropamine), have been sold online as designer drugs. However, how deoxymethoxetamine and methoxisopropamine act on NMDARs remains unknown. In this study, we first performed in silico docking studies of NMDARs, and deoxymethoxetamine and methoxisopropamine in addition to the major methoxetamine metabolites, 2-amino-2-(3-methoxyphenyl)-cyclohexanone (N-desethyl methoxetamine) and 2-(ethylamino)-2-(3-hydroxyphenyl)-cyclohexanone (O-desmethyl methoxetamine). The docking study suggested each compound interacts with NMDARs. We also determined the half-maximal inhibitory concentration (IC50s) of the methoxetamine-related compounds for NMDARs using NMDAR-expressing cartwheel interneurons of mice and patch-clamp recordings. We found that the IC50s of methoxetamine, deoxymethoxetamine, methoxisopropamine, N-desethyl methoxetamine, and O-desmethyl methoxetamine for NMDARs were 0.524, 0.679, 0.661, 1.649, and 0.227 µM, respectively. These results indicate that the methoxetamine-related compounds act as potent NMDAR blockers. Thus, deoxymethoxetamine and methoxisopropamine, both of which may cause damage by blocking NMDARs, are serious concerns. N-Desethyl methoxetamine and O-desmethyl methoxetamine may cause several adverse effects when methoxetamine is metabolized.
Subject(s)
Cyclohexanones , Receptors, N-Methyl-D-Aspartate , Cyclohexanones/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Cyclohexylamines/pharmacologyABSTRACT
To evaluate the biological effects of Porphyra tenera (P. tenera), we tried to confirm the possibility that the intake of P. tenera could modulate cognitive and intestinal functions in PM2.5-induced cognitive decline mice. P. tenera attenuated PM2.5-induced learning and memory impairment through antioxidant and anti-inflammatory effects by regulating the mitochondrial function and TLR-initiated NF-κB signaling. In addition, P. tenera effectively alleviated Aß production/tau phosphorylation by inhibiting the JNK phosphorylation. Also, the bioactive constituents of P. tenera determined the sulfated galactan, mycosporine-like amino acids (MAAs), and chlorophyll derivatives. Moreover, the bioactive compounds of P. tenera by gut fermentation protected against gut dysbiosis and intestinal tight junction damage with a decrease in inflammatory response and short-chain fatty acid production. Based on these results, our findings suggest that P. tenera with sulfated galactan and MAAs is a potential material for cognitive function improvement.
Subject(s)
Cognitive Dysfunction , Porphyra , Rhodophyta , Animals , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/prevention & control , Cyclohexanones/pharmacology , Galactans , Glycine , Mice , Particulate Matter , Porphyra/chemistryABSTRACT
Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kß. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1-3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.
Subject(s)
Cyclohexanones , Macrophages , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Cyclohexanones/metabolism , Cyclohexanones/pharmacology , Cytokines/metabolism , Humans , Inflammation/metabolism , Macrophages/metabolismABSTRACT
Prostate cancer is a major cause of cancer-related mortality in men in developed countries. The compound, 4-acetylantroquinonol B (4AAQB), is isolated from Antrodia cinnamomea (commonly known as Niu-Chang-Chih), which has been shown to inhibit cancer growth. However, the anticancer activity of 4AAQB has not previously been examined in prostate cancer. This study aimed to investigate the effect of 4AAQB on cancer and angiogenesis, as well as to explore its mechanism of action. Human prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) were used in cell viability, cell migration, and cell cycle functional assays to evaluate the anticancer and antiangiogenic efficacy of 4AAQB in vitro. The effects of 4AAQB in vivo were determined using xenograft and angiogenesis models. The signaling events downstream of 4AAQB were also examined. The 4AAQB compound inhibited PC3 cell growth and migration, and reduced in vivo cancer growth, as shown in a subcutaneous xenograft model. Furthermore, 4AAQB inhibited HUVEC migration, tube formation, and aortic ring sprouting; it also reduced neovascularization in a Matrigel implant angiogenesis assay in vivo. The 4AAQB compound also decreased metastasis in the PC3 prostate cancer model in vivo. Serum or vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/Ak strain transforming (Akt), and extracellular signal-regulated kinase ½ (ERK ½) phosphorylation were attenuated by 4AAQB in both PC3 and HUVEC. In conclusion, 4AAQB is a potential candidate for prostate cancer therapy.
Subject(s)
4-Butyrolactone/analogs & derivatives , Angiogenesis Inhibitors/administration & dosage , Cyclohexanones/administration & dosage , Prostatic Neoplasms/drug therapy , Signal Transduction/drug effects , 4-Butyrolactone/administration & dosage , 4-Butyrolactone/pharmacology , Angiogenesis Inhibitors/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclohexanones/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Male , PC-3 Cells , Phosphatidylinositol 3-Kinase/metabolism , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Spirooxindoles are privileged scaffolds in medicinal chemistry, which were identified through Wang's pioneering work as inhibitors of MDM2-p53 interactions. OBJECTIVE: To design and synthesize 2,6-diarylidenecyclohexanones and dispiro[oxindole-cyclohexanone]- pyrrolidines having potential antitumor effect. METHODS: Dispiro[oxindole-cyclohexanone]-pyrrolidines 6a-h were synthesized in a regioselective manner via 1,3-dipolar cycloaddition reaction of 2,6-diarylidenecyclohexanones 3a-h, isatin, and sarcocine. Compounds 6a-h were alkylated to give (7-10)a,b. All compounds were evaluated in vitro for their antitumor activity and cytotoxic selectivity against breast cancer cell lines (MCF-7 and MDA-MB-231), breast fibrosis cell line (MCF10a), and placental cancer cell line (JEG-3). Molecular modeling inside the MDM2 binding site was performed using AutoDock4.2. RESULTS: Synthesized compounds showed antitumor activity comparable to tamoxifen and compounds 3a,b,f,g and 9a,b showed selective cytotoxicity against tumor cells but reduced toxicity toward MCF-10a cells. Molecular modelling shows that both classes of synthesized compounds are predicted to fit the deep hydrophobic cleft on the surface of MDM2 and mimic the interactions between p53 and MDM2. CONCLUSION: The synthesized compounds have antitumor activity against MCF-7, MDA-MB-231, and JEG-3. Few compounds showed a selective cytotoxic effect and may have the potential to inhibit MDM2 and stimulate p53. In the future, studies regarding the optimization of medicinal chemistry as well as mechanistic studies will be conducted to enhance the inhibition effect of identified compounds and elucidate their mechanism of action.
Subject(s)
Antineoplastic Agents , Spiro Compounds , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation , Cyclohexanones/pharmacology , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Oxindoles/chemistry , Oxindoles/pharmacology , Placenta/metabolism , Pregnancy , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
As part of our search for bioactive metabolites from understudied marine microorganisms, the new chlorinated metabolite chlovalicin B (1) was isolated from liquid cultures of the marine basidiomycete Digitatispora marina, which was collected and isolated from driftwood found at Vannøya, Norway. The structure of the novel compound was elucidated by spectroscopic methods including 1D and 2D NMR and analysis of HRMS data, revealing that 1 shares its molecular scaffold with a previously isolated compound, chlovalicin. This represents the first compound isolated from the Digitatispora genus, and the first reported fumagillin/ovalicin-like compound isolated from Basidiomycota. Compound 1 was evaluated for antibacterial activities against a panel of five bacteria, its ability to inhibit bacterial biofilm formation, for antifungal activity against Candida albicans, and for cytotoxic activities against malignant and non-malignant human cell lines. Compound 1 displayed weak cytotoxic activity against the human melanoma cell line A2058 (~50% survival at 50 µM). No activity was detected against biofilm formation or C. albicans at 50 µM, or against bacterial growth at 100 µM nor against the production of cytokines by the human acute monocytic leukemia cell line THP-1 at 50 µM.
Subject(s)
Anti-Bacterial Agents , Antifungal Agents , Bacteria/growth & development , Basidiomycota/chemistry , Candida albicans/growth & development , Sesquiterpenes , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Cyclohexanones/chemistry , Cyclohexanones/isolation & purification , Cyclohexanones/pharmacology , Epoxy Compounds/chemistry , Epoxy Compounds/isolation & purification , Epoxy Compounds/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacologyABSTRACT
Poupartia borbonica is an endemic tree from the Mascarene Islands that belongs to the Anacardiaceae family. The leaves of this plant were phytochemically studied previously, and isolated alkyl cyclohexenone derivatives, poupartones Aâ-âC, demonstrated antiplasmodial and antimalarial activities. In addition to their high potency against the Plasmodium sp., high toxicity on human cells was also displayed. The present study aims to investigate in more detail the cytotoxicity and pharmacological interest of poupartone B, one of the most abundant derivatives in the leaves of P. borbonica. For that purpose, real-time live-cell imaging of different human cancer cell lines and normal fibroblasts, treated or not treated with poupartone B, was performed. A potent inhibition of cell proliferation associated with the induction of cell death was observed. A detailed morphological analysis of different adherent cell lines exposed to high concentrations of poupartone B (1â-â2 µg/mL) demonstrated that this compound induced an array of cellular alterations, including a rapid retraction of cellular protrusions associated with cell rounding, massive cytoplasmic vacuolization, loss of plasma membrane integrity, and plasma membrane bubbling, ultimately leading to paraptosis-like cell death. The structure-activity relation of this class of compounds, their selective toxicity, and pharmacological potential are discussed.