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Bioorganic & Medicinal Chemistry Letters Jun 2021Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the G-coupled P2Y receptor (P2YR) were synthesized using a Sonogashira...
Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the G-coupled P2Y receptor (P2YR) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2YR-expressing astrocytoma cells elicited by native P2YR agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3-5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2YR affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2YR, which is a target for inflammatory, neurodegenerative and metabolic diseases.
Topics: Benzopyrans; Dose-Response Relationship, Drug; Humans; Molecular Structure; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2; Structure-Activity Relationship
PubMed: 33831560
DOI: 10.1016/j.bmcl.2021.128008 -
Journal of the American Chemical Society Nov 2019Selective access to a targeted isomer is often critical in the synthesis of biologically active molecules. Whereas small-molecule reagents and catalysts often act with...
Selective access to a targeted isomer is often critical in the synthesis of biologically active molecules. Whereas small-molecule reagents and catalysts often act with anticipated site- and stereoselectivity, this predictability does not extend to enzymes. Further, the lack of access to catalysts that provide complementary selectivity creates a challenge in the application of biocatalysis in synthesis. Here, we report an approach for accessing biocatalysts with complementary selectivity that is orthogonal to protein engineering. Through the use of a sequence similarity network (SSN), a number of sequences were selected, and the corresponding biocatalysts were evaluated for reactivity and selectivity. With a number of biocatalysts identified that operate with complementary site- and stereoselectivity, these catalysts were employed in the stereodivergent, chemoenzymatic synthesis of azaphilone natural products. Specifically, the first syntheses of trichoflectin, deflectin-1a, and lunatoic acid A were achieved. In addition, chemoenzymatic syntheses of these azaphilones supplied enantioenriched material for reassignment of the absolute configuration of trichoflectin and deflectin-1a based on optical rotation, CD spectra, and X-ray crystallography.
Topics: Benzopyrans; Biocatalysis; Biological Products; Pigments, Biological; Stereoisomerism
PubMed: 31692339
DOI: 10.1021/jacs.9b09385 -
Journal of Diabetes Research 2018Chronic inflammatory diseases like diabetes are on a rise in the Western world. Based on the tsunami of new cases every year, new therapeutic measures must be... (Review)
Review
Chronic inflammatory diseases like diabetes are on a rise in the Western world. Based on the tsunami of new cases every year, new therapeutic measures must be considered. A promising avenue might involve the attenuation of underlying inflammation through natural health products (NHPs). This is because most NHPs have a rich history in traditional medicine and might be considered safer under appropriate doses and conditions. However, the biggest impediment in NHP research is that rarely do these products come with verified health benefits or dosing schedules established through modern scientific research. Fulvic acid (FvA), one such NHP, comes from humic substances produced by microorganisms in soil. Traditional medicine and modern research claim FvA can modulate the immune system, influence the oxidative state of cells, and improve gastrointestinal function; all of which are hallmarks of diabetes. This minireview outlines the available peer-reviewed research on FvA and examines its anecdotal health claims. We show that although available research has been minimal, there is substantial evidence to pursue FvA research in preventing chronic inflammatory diseases, including diabetes.
Topics: Benzopyrans; Diabetes Mellitus; Humans; Inflammation; Medicine, Traditional
PubMed: 30276216
DOI: 10.1155/2018/5391014 -
Vascular Health and Risk Management 2006Nebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and a nitric oxide... (Review)
Review
Nebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and a nitric oxide (NO)-potentiating, vasodilatory effect that is unique among beta-blockers currently available to clinicians (nebivolol is approved in Europe and is currently under review in the US). A NO-potentiating agent such as nebivolol may have an important role in hypertensive populations with reduced endothelial function such as diabetics, African-Americans and those with vascular disease. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-isomer; in contrast, l-nebivolol is far more potent in facilitating NO release. Nebivolol is unique among beta-blockers in that, at doses < 10 mg, it does not inhibit the increase in heart rate normally seen with exercise. The efficacy ofnebivolol has been tested successfully in clinical trials against other agents including other beta-blockers, angiotensin-converting enzyme-inhibitors and calcium channel antagonists in patients with hypertension, angina, and congestive heart failure. The tolerability of nebivolol has been shown to be superior to that of atenolol and metoprolol. In controlled clinical trials, nebivolol has a side effect profile that is similar to placebo, in particular as it relates to fatigue and sexual dysfunction. This article will review published clinical data regarding this cardioselective beta-blocker.
Topics: Adrenergic beta-Antagonists; Benzopyrans; Blood Pressure; Cardiovascular Diseases; Endothelium, Vascular; Ethanolamines; Heart Rate; Humans; Hypertension; Nebivolol; Nitric Oxide; Vasodilation
PubMed: 17326335
DOI: 10.2147/vhrm.2006.2.3.303 -
Molecules (Basel, Switzerland) May 2016γ-l-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl]amino]-3-oxopropyl]-l-cys...
γ-l-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl]amino]-3-oxopropyl]-l-cysteinylglycine sodium salt (ESeroS-GS) is a water-soluble derivative of α-tocopherol (vitamin E). We reported previously that ESeroS-GS can act as an anti-inflammatory agent and can induce cell death in breast cancer cells. However, the potential antioxidant capacities of ESeroS-GS remain elusive. Here, we measured its scavenging effects on free radicals and evaluated its protective effects on neuronal cells against oxidative stress. The results indicated that ESeroS-GS effectively scavenged both 2,2'-azinobis(3-ethylbenzothiazoline)-6-sulfonate free radicals (ABTS(•+)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals, and attenuated H₂O₂-induced neuronal cell death. H₂O₂ treatment induced lysosomal membrane permeabilization rapidly, and caused the redistribution of lysosomal proteases, which were responsible for the neuronal cell death. ESeroS-GS abolished the interaction between tBid and the lysosomal membranes, blocked the translocation of tBid to the lysosomal membranes, decreased its oligomerization within the membrane circumstances, prevented the lysosomal membrane permeabilization, and thus attenuated the neuronal cell death. These data suggest that ESeroS-GS protected the neuronal cells from oxidative stress by stabilizing lysosomal membranes, and thus might act as a novel neuroprotector for neuronal diseases associated with oxidative stress.
Topics: Antioxidants; Apoptosis; Benzopyrans; Benzothiazoles; Biphenyl Compounds; Cell Membrane Permeability; Free Radical Scavengers; Humans; Hydrogen Peroxide; Indoles; Lysosomes; Neurons; Oxidative Stress; Picrates; Sulfonic Acids; Vitamin E
PubMed: 27231890
DOI: 10.3390/molecules21060637 -
Molecules (Basel, Switzerland) Oct 2022This study aimed to synthesize, characterize, and explore the eco-friendly and antifungal potential of precocenes and their derivatives. The organic synthesis of the...
This study aimed to synthesize, characterize, and explore the eco-friendly and antifungal potential of precocenes and their derivatives. The organic synthesis of the mono-O-alkyl-2,2-dimethyl 2-1-chromene series, including the natural product precocene I, and the di--alkyl 2,2-dimethyl-2-1-chromene series, including the natural 2-1-chromenes precocenes II and III, was achieved. The synthetic compounds were subjected to spectroscopic analysis, HNMR,CNMR, and mass characterization. The antifungal activity of synthesized precocenes I, II, and III, as well as their synthetic intermediates, was evaluated by the poison food technique. Precocene II (EC 106.8 µg × mL and 4.94 µg mL), and its regioisomers (EC 97.18 µg × mL and 35.30 µg × mL) and (EC 170.58 × µg mL), exhibited strong fungitoxic activity against and . Some of the novel chromenes, and , which had never been evaluated before, yielded stronger fungitoxic effects. Finally, docking simulations for compounds with promising fungitoxic activity were subjected to structure-activity relationship analyses against the polygalactouronases and voltage-dependent anion channels. Conclusively, precocenes and their regioisomers demonstrated promising fungitoxic activity; such compounds can be subjected to minor structural modifications to yield promising and novel fungicides.
Topics: Antifungal Agents; Rhizoctonia; Fungicides, Industrial; Structure-Activity Relationship; Benzopyrans
PubMed: 36364004
DOI: 10.3390/molecules27217177 -
Acta Pharmacologica Sinica Apr 2022Bergenin is a natural PPARγ agonist that can prevent neutrophil aggregation, and often be used in clinics for treating respiratory diseases. Recent data show that Th17...
Bergenin is a natural PPARγ agonist that can prevent neutrophil aggregation, and often be used in clinics for treating respiratory diseases. Recent data show that Th17 cells are important for neutrophil aggregation and asthma through secreting IL-17A. In this study, we investigated the effects of bergenin on Th17 differentiation in vitro and subsequent neutrophilic asthma in mice. Naïve T cells isolated from mouse mesenteric lymph nodes were treated with IL-23, TGF-β, and IL-6 to induce Th17 differentiation. We showed that in naïve T cells under Th17-polarizing condition, the addition of bergenin (3, 10, 30 μM) concentration-dependently decreased the percentage of CD4 IL-17A T cells and mRNA expression of specific transcription factor RORγt, and function-related factors IL-17A/F, IL-21, and IL-22, but did not affect the cell vitality and apoptosis. Furthermore, bergenin treatment prevented GLS1-dependent glutaminolysis in the progress of Th17 differentiation, slightly affected the levels of SLC1A5, SLC38A1, GLUD1, GOT1, and GPT2. Glutamine deprivation, the addition of glutamate (1 mM), α-ketoglutarate (1 mM), or GLS1 plasmid all significantly attenuated the above-mentioned actions of bergenin. Besides, we demonstrated that bergenin (3, 10, and 30 μM) concentration-dependently activated PPARγ in naïve T cells, whereas PPARγ antagonist GW9662 and siPPARγ abolished bergenin-caused inhibition on glutaminolysis and Th17 differentiation. Furthermore, we revealed that bergenin inhibited glutaminolysis by regulating the level of CDK1, phosphorylation and degradation of Cdh1, and APC/C-Cdh1-mediated ubiquitin-proteasomal degradation of GLS1 after activating PPARγ. We demonstrated a correlation existing among bergenin-affected GLS1-dependent glutaminolysis, PPARγ, "CDK1-APC/C-Cdh1" signaling, and Th17 differentiation. Finally, the therapeutic effect and mechanisms for bergenin-inhibited Th17 responses and neutrophilic asthma were confirmed in a mouse model of neutrophilic asthma by administration of GW9662 or GLS1 overexpression plasmid in vivo. In conclusion, bergenin repressed Th17 differentiation and then alleviated neutrophilic asthma in mice by inhibiting GLS1-dependent glutaminolysis via regulating the "CDK1-APC/C-Cdh1" signaling after activating PPARγ.
Topics: Animals; Asthma; Benzopyrans; Cell Differentiation; Glutaminase; Mice; PPAR gamma; Th17 Cells
PubMed: 34267342
DOI: 10.1038/s41401-021-00717-1 -
Molecules (Basel, Switzerland) May 2012This review covers the construction of drug-like 2H-benzopyrans and related libraries using solid-phase parallel synthesis. In this context, the preparation of... (Review)
Review
This review covers the construction of drug-like 2H-benzopyrans and related libraries using solid-phase parallel synthesis. In this context, the preparation of substituted benzopyrans such as mono-, di- and trisubstituted benzopyran derivatives and additional ring-fused benzopyrans such as benzopyranoisoxazoles, benzopyranopyrazoles, six-membered ring-fused benzopyrans, and polycyclic benzopyrans are highlighted.
Topics: Benzopyrans; Combinatorial Chemistry Techniques; Drug Discovery; Molecular Structure; Pharmaceutical Preparations; Small Molecule Libraries; Solid-Phase Synthesis Techniques
PubMed: 22572931
DOI: 10.3390/molecules17055467 -
Marine Drugs Sep 2021To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae sp. Two new...
To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae sp. Two new azaphilones, 8a--hypocrellone A (), 8a--eupenicilazaphilone C (), together with five known azaphilones, hypocrellone A (), eupenicilazaphilone C (), ((1,3)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (), sclerotiorin (), and isochromophilone IV () were isolated from the alga-derived fungus . The structures of isolated azaphilones (-) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 μM of compounds , , and inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds and respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-β.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Aquatic Organisms; Benzopyrans; Cell Line, Tumor; Fibroblasts; Functional Food; Microalgae; Neuroblastoma; Penicillium; Pigments, Biological; Structure-Activity Relationship
PubMed: 34677428
DOI: 10.3390/md19100529 -
The Journal of Biological Chemistry Aug 2020Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid...
Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aβ deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aβ oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.
Topics: Amyloid beta-Peptides; Animals; Benzopyrans; Brain; Male; Mice; Protein Aggregates; Protein Aggregation, Pathological; Vitamin E
PubMed: 32616652
DOI: 10.1074/jbc.RA120.013303