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•Trifluoromethyl- and pentafluorosulfanyl-substituted curcuminoids were prepared and tested for anti-parasitic activity.•T. gondii and L. major parasite growth was inhibited at ...nanomolar concentrations.•High selectivity was observed for various derivatives.•Docking of curcuminoids into L. major PTR1 revealed key interactions via fluorine atoms.•Physicochemical properties of curcuminoids were determined.
A series of the title curcuminoids with structural variance in the heteroatom of the cycloalkanone and the p-substituents of the phenyl rings were tested for their activities against Leishmania major and Toxoplasma gondii parasites. The majority of them showed high activities against both parasite forms with EC50 values in the sub-micromolar concentration range. Bis(p-pentafluorothio)-substituted 3,5-di(E)-benzylidenepiperidin-4-one 1b was not just noticeable antiparasitic, but also exhibited a considerable selectivity for L. major promastigotes over normal Vero cells. While derivatives differing only in the p-phenyl substituents being CF3 or SF5 showed similar antiparasitic activities, the cyclic ketone hub was more decisive both for the anti-parasitic activities and the selectivities for the parasites vs. normal cells. QSAR calculations confirmed the observed structure–activity relations and suggested structural variations for a further improvement of the antiparasitic activity. Docking studies based on DFT calculations revealed L. major pteridine reductase 1 as a likely molecular target protein of the title compounds.
Inhibition of dengue virus by curcuminoids Balasubramanian, Anuradha; Pilankatta, Rajendra; Teramoto, Tadahisa ...
Antiviral research,
02/2019, Letnik:
162
Journal Article
Recenzirano
Odprti dostop
The dengue virus is considered to be a globally important human pathogen prevalent in tropical and subtropical regions of the world. According to a recent estimate, the disease burden due to DENV ...infections is ∼390 million infections per year globally in ∼100 countries including the southern US, Puerto Rico and Hawaii, resulting in nearly ∼25,000 deaths mostly among children. Despite the significant morbidity and mortality that results from DENV infections, there is currently no effective chemotherapeutic treatment for DENV infections. We identified curcumin as an inhibitor of DENV2 NS2B/NS3protease in a previous high-throughput screening (HTS) campaign. We synthesized four analogues of curcumin (curcuminoids) and tested the in vitro protease inhibition activity and inhibition of replication by cell-based assays. The results revealed that curcumin is a weak inhibitor of the viral protease. However, the analogues exhibited more potent inhibition of DENV infectivity in plaque assays suggesting that the cellular pathway(s) required for viral replication and/or assembly are targeted by these compounds. Further analysis shows that inhibition of genes involved in lipid biosynthesis, and of actin polymerization by curcuminoids, are likely to be involved as their mode of action in DENV2-infected cells. Three of the curcumin derivatives possess good selectivity indices (SI) (>10) when compared to the parent curcumin.
•Curcumin, a natural product, has many medicinal properties including antiviral activities against DNA and RNA viruses.•Curcumin with a β-diketone moiety undergoes retro-aldol decomposition in plasma pH.•To improve its stability, monoketone analogues were synthesized and their anti-dengue viral activities were tested.•Three new curcuminoids had better antiviral activities than native curcumin.•Curcuminoids decreased lipogenic acetyl CoA carboxylase and fatty acid synthase gene expression.
A systematic study of the asymmetric transfer hydrogenations of functionalized acetylenic ketones and diketones has been completed, together with a total synthesis of (S,S)-(-)-yashabushidiol B. In ...several cases, excellent enantioselectivities and yields were achieved.
Five new cyclic diarylheptanoids (platycary A-E, compounds
-
) and three previously identified analogues (i.e., phttyearynol (compound
), myricatomentogenin (compound
), and juglanin D (compound
)) ...were isolated from the stem bark of
. The structures of these compounds were determined using NMR, HRESIMS, and electronic circular dichroism (ECD) data. The cytotoxicity of compounds
-
and their ability to inhibit nitric oxide (NO) production, as well as protect against the corticosterone-induced apoptosis of Pheochromocytoma (PC12) cells, were evaluated in vitro using the appropriate bioassays. Compounds
and
significantly inhibited the corticosterone-induced apoptosis of PC12 cells at a concentration of 20 μΜ.
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Total methanolic extract of Alnus japonica fruits exhibited significant anti-adipogenic activities in 3T3-L1 cells. A new cyclic diarylheptanoid (1) along with ten known compounds ...(2–11) were isolated by activity-guided fractionation. Compound 1, determined to be 4-hydroxy-alnus-3,5-dione, showed the most potent anti-adipogenic effect. Compound 1 significantly down-regulated expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and sterol regulatory element binding protein 1 (SREBP1c) in 3T3-L1 cells, as determined by quantitative real-time PCR and Western blot analysis. Furthermore, compound 1 suppressed mRNA expression of C/EBPβ and C/EBPδ during the early stage of adipogenesis as well as stearoyl coenzyme A desaturase 1 (SCD-1) and fatty acid synthase (FAS), target genes of SREBP1c. Upon investigating the mechanism of natural products, we propose that cyclic diarylheptanoid (1), the most potent constituent of A. japonica, can be a potent therapeutic agent against obesity through anti-adipogenesis via down-regulation of PPARγ, C/EBPα, and SREBP1c signaling.
Osteoporosis is caused by a functional imbalance between osteoblasts and osteoclasts. The increased activation of osteoclasts that is a hallmark of osteoporosis results in the progressive loss of ...bone mass and therefore in an increased susceptibility to bone fractures. Diarylheptanoids are a group of phytoestrogens that have been isolated from a number of plant species, including the rhizomes of Curcuma comosa Roxb. In this study, the effect of one of diarylheptanoids, (3S)-1-(3,4-dihydroxyphenyl)-3-hydroxy-7-phenyl-(6E)-6-heptene (DHPH), was investigated for anti-inflammatory and anti-osteoclastogenic activity. DHPH significantly inhibited nitric oxide production in RAW264.7 cell line following their activation by lipopolysaccharide and interferon-γ, with no cytotoxicity. In primary mouse bone-marrow-derived macrophage precursors, DHPH suppressed osteoclastogenesis induced by receptor activator of nuclear factor-κB (RANK) ligand at an inhibitory concentration 50 of 325±1.37nM. DHPH treatment delayed and reduced the expression of master regulators of osteoclast differentiation, NFATc1 and c-Fos. Consistent with this result, the mRNA level of cathepsin K, associated with osteoclast differentiation, was decreased whereas the reduction in the mRNA of irf8, a negative regulator of osteoclast differentiation, was similar to that measured in the vehicle-treated control cells. DHPH reduced the phosphorylation of p38 MAPK, ERK (p44/42). Furthermore, DHPH suppressed the bone absorption activity of osteoclasts and enhanced osteoblast differentiation. Taken together, DHPH interrupts the immediate downstream signaling cascade of RANK and interferes with osteoclast differentiation and its function while enhances osteoblast differentiation. These results demonstrate the potential of this diarylheptanoid as a new therapeutic agent in osteoporosis.
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We investigated the effect of a phytoestrogen, (3
)-1,7-diphenyl-(4
,6
)-4,6-heptadien-3-ol (DPHD), from
Roxb. (Zingiberaceae family) on the adipogenic differentiation of mesenchymal progenitors, ...human bone marrow-derived mesenchymal stem cells (hBMSCs). DPHD inhibited adipocyte differentiation of hBMSCs by suppressing the expression of genes involved in adipogenesis. DPHD at concentrations of 0.1, 1, and 10 μM significantly decreased triglyceride accumulation in hBMSCs to 7.1 ± 0.2, 6.3 ± 0.4, and 4.9 ± 0.2 mg/dL, respectively, compared to the nontreated control (10.1 ± 0.9 mg/dL) (
< 0.01). Based on gene expression profiling, DPHD increased the expression of several genes involved in the Wnt/β-catenin signaling pathway, a negative regulator of adipocyte differentiation in hBMSCs. DPHD also increased the levels of essential signaling proteins which are extracellular signal-regulated kinases 1 and 2 (ERK1/2) and glycogen synthase kinase 3 beta (GSK-3β) that link estrogen receptor (ER) signaling to Wnt/β-catenin signaling. In conclusion, DPHD exhibited the anti-adipogenic effect in hBMSCs by suppression of adipogenic markers in hBMSCs through the activation of ER and Wnt/β catenin signaling pathways. This finding suggests the potential role of DPHD in preventing bone marrow adiposity which is one of the major factors that exacerbates osteoporosis in postmenopause.
In a continuing search for bioactive constituents from Dioscoreaceae medicinal plants, two new cyclic diarylheptanoids, diosniponol A (1) and B (2), together with 10 known compounds (3–12) were ...isolated from the rhizomes of Dioscorea nipponica. The structures of these new compounds were determined by spectroscopic analyses, including extensive two-dimensional nuclear magnetic resonance, high-resolution mass spectrometry, and optical rotation. All isolated compounds 1–12 were evaluated for their effects on nitric oxide (NO) production in murine microglia cell line BV-2. Compounds 8 and 11 showed potent inhibitory activities on NO production (IC50 13.36 and 14.36μM, respectively) without cell toxicity in lipopolysaccharide-activated BV-2 cells.
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Using curcuminoids as lead compounds, fifty-nine curcuminoid derivatives with different side chains at the phenolic moiety were synthesized. All compounds were investigated for their ...histone deacetylase (HDAC) inhibitory activities. The potent pan-HDAC inhibitors were further tested against three human cancer cell lines including Hela, HCT116 and MCF-7 with MTT-based assay. The bisethylamide 4z and the mono-sec-butyl derivative 5j manifested good antiproliferative activities against HCT116 cancer cells with the IC50 values as 14.60 ± 1.19 μg/mL and 7.33 ± 0.98 μg/mL, respectively. Molecular docking study of both compounds with Class I HDACs revealed that the compounds might bind tightly to the binding pocket of HDAC2. These findings suggested that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.
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