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Clinical Interventions in Aging Dec 2010Heart failure is a common and disabling condition with morbidity and mortality that increase dramatically with advancing age. Large observational studies, retrospective... (Review)
Review
Heart failure is a common and disabling condition with morbidity and mortality that increase dramatically with advancing age. Large observational studies, retrospective subgroup analyses and meta-analyses of clinical trials in systolic heart failure, and recently published randomized studies have provided data supporting the use of beta-blockers as a baseline therapy in heart failure in the elderly. Despite the available evidence about beta-blockers, this therapy is still less frequently used in elderly compared to younger patients. Nebivolol is a third-generation cardioselective beta-blocker with L-arginine/nitric oxide-induced vasodilatory properties, approved in Europe and several other countries for the treatment of essential hypertension, and in Europe for the treatment of stable, mild, or moderate chronic heart failure, in addition to standard therapies in elderly patients aged 70 years old or older. The effects of nebivolol on left ventricular function in elderly patients with chronic heart failure (ENECA) and the study of effects of nebivolol intervention on outcomes and rehospitalization in seniors with heart failure (SENIORS) have been specifically aimed to assess the efficacy of beta-blockade in elderly heart failure patients. The results of these two trials demonstrate that nebivolol is well tolerated and effective in reducing mortality and morbidity in older patients, and that the beneficial clinical effect is present also in patients with mildly reduced ejection fraction. Moreover, nebivolol appears to be significantly cost-effective when prescribed in these patients. However, further targeted studies are needed to better define the efficacy as well as safety profile in frail and older patients with comorbid diseases.
Topics: Adrenergic beta-1 Receptor Antagonists; Aging; Antihypertensive Agents; Benzopyrans; Chronic Disease; Cost-Benefit Analysis; Ethanolamines; Europe; Female; Heart Failure; Humans; Hypertension; Male; Nebivolol; Treatment Outcome; Ventricular Function, Left
PubMed: 21152240
DOI: 10.2147/CIA.S4482 -
Journal of Medicinal Chemistry Apr 2019σ and/or σ receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with...
σ and/or σ receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ receptor affinity and σ:σ selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. cis-configured 2-benzopyran cis-11b bearing a methoxy group and a tertiary cyclohexylmethylamino moiety showed the highest σ affinity ( K = 1.9 nM) of this series of compounds. In a Ca influx assay, cis-11b behaved as a σ antagonist. cis-11b reveals high selectivity over σ and opioid receptors. The interactions of the novel σ ligands were analyzed on the molecular level using the recently reported X-ray crystal structure of the σ receptor protein. The protonated amino moiety forms a persistent salt bridge with E172. The spiro[benzopyran-1,1'-cyclohexane] scaffold and the cyclohexylmethyl moiety occupy two hydrophobic pockets. Exchange of the N-cyclohexylmethyl moiety by a benzyl group led unexpectedly to potent and selective μ-opioid receptor ligands.
Topics: Benzopyrans; Binding Sites; Crystallography, X-Ray; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Dynamics Simulation; Protein Structure, Tertiary; Receptors, Opioid, mu; Receptors, sigma; Spiro Compounds; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 30939014
DOI: 10.1021/acs.jmedchem.9b00449 -
Chemical Biology & Drug Design Feb 2021Spiropyrans have been extensively investigated because of their thermo- and photochromic characteristics, but their biotherapeutic properties have not been explored...
Spiropyrans have been extensively investigated because of their thermo- and photochromic characteristics, but their biotherapeutic properties have not been explored much. We report anti-proliferative properties of a novel 3,3'-azadimethylene dinaphthospiropyran 11. Dibenzospiropyrans and dinaphthospiropyrans were synthesized by a simple and expedient method using acid-catalyzed aldol condensation of salicylaldehyde and 2-hydroxy-1-naphthaldehyde, respectively, with cyclic ketones. Together with structural elucidation by 2D NMR and X-ray crystallography studies, we provide a putative mechanism for their formation. Compound 11 showed solvatochromism and exhibited altered spectral characteristics depending on the pH. In acidic conditions, 11 remains in open form, whereas upon alkalinization it reverts back to closed form. Based on the in vitro anti-proliferative activity in H441, HCT-116, MiaPaCa-2, and Panc-1 cancer cell lines, 11 was submitted to further investigation. It reduced HCT116 colonosphere formation and demonstrated induction of caspase cascade, suggesting apoptosis. In vitro proliferation assays also suggested that HCl and trifluoroacetate salts of 11 are more effective. Treatment of mice carrying HCT-116 xenografts with 11 (5 µg/day, intraperitoneal for 3 weeks) suppressed tumor growth by 62%. Overall, the results reveal a new series of structurally complex, but relatively easy to synthesize molecules of which compound 11 represents a lead for anticancer development.
Topics: Animals; Antineoplastic Agents; Apoptosis; Benzopyrans; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Indoles; Mice; Molecular Conformation; Nitro Compounds; Transplantation, Heterologous
PubMed: 32909340
DOI: 10.1111/cbdd.13785 -
Scientific Reports Dec 2022In the present study, the FeO@Glycerol-Cu complex supported magnetically as a nanoparticle was prepared by grafting. Firstly, FeO NPs were synthesized by FeCl.6HO and...
In the present study, the FeO@Glycerol-Cu complex supported magnetically as a nanoparticle was prepared by grafting. Firstly, FeO NPs were synthesized by FeCl.6HO and FeCl.4HO according to the reported method, and subsequently, the prepared MNP with 3-chloropropyltrimethoxysilane. After that, the support-glycerol was functionalized on the surface of MNP-(CH)Cl for graft and stabilization of copper metal. Our purpose is to use the FeO@Glycerol-Cu as a green, recoverable, novel, and affordable nanocatalyst in the effective synthesis of 2-amino-4H-chromenes. FT-IR, XRD, TGA, BET, VSM, TEM, and SEM-EDX techniques were examined to characterize this nanocatalyst. This result demonstrates that copper and organic compounds have appropriately reacted, with the support of MNP-(CH)Cl, and the crystalline structure have preserved in the MNP-(CH)Cl/Glycerol-Cu nanocatalyst confirmed the formation of the base Cu complex grafted on the surface of the nanoparticles. Finally, as can be seen, the nanoparticle size is 5-15 nm. This heterogeneous nanocatalyst illustrated excellent recyclable behavior, and can be used several times without notable reduction of its activity.
Topics: Glycerol; Copper; Benzopyrans; Spectroscopy, Fourier Transform Infrared; Magnetic Phenomena
PubMed: 36550173
DOI: 10.1038/s41598-022-26769-9 -
Marine Drugs Apr 2020The marine-derived fungus , isolated from sediment collected from the Canyon at Dahab, Red Sea, yielded two new chlorinated azaphilones, falconensins O and P ( and ) in...
The marine-derived fungus , isolated from sediment collected from the Canyon at Dahab, Red Sea, yielded two new chlorinated azaphilones, falconensins O and P ( and ) in addition to four known azaphilone derivatives (-) following fermentation of the fungus on solid rice medium containing 3.5% NaCl. Replacing NaCl with 3.5% NaBr induced accumulation of three additional new azaphilones, falconensins Q-S (-) including two brominated derivatives ( and ) together with three known analogues (-). The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and HRESIMS data as well as by comparison with the literature. The absolute configuration of the azaphilone derivatives was established based on single-crystal X-ray diffraction analysis of , comparison of NMR data and optical rotations as well as on biogenetic considerations. Compounds , -, and showed NF-κB inhibitory activity against the triple negative breast cancer cell line MDA-MB-231 with IC values ranging from 11.9 to 72.0 µM.
Topics: Animals; Antineoplastic Agents; Aquatic Organisms; Aspergillus; Benzopyrans; Cell Line, Tumor; Geologic Sediments; Indian Ocean; Inhibitory Concentration 50; Pigments, Biological
PubMed: 32290208
DOI: 10.3390/md18040204 -
Molecules (Basel, Switzerland) Jan 2021The dichloromethane extract from leaves of (Rutaceae), endemic to the Hawaiian island of Kaua'i, yielded four new and three previously known acetophenones and...
The dichloromethane extract from leaves of (Rutaceae), endemic to the Hawaiian island of Kaua'i, yielded four new and three previously known acetophenones and 2-chromenes, all found for the first time in . The structures of the new compounds obtained from the dichloromethane extract after purification by chromatographic methods were unambiguously elucidated by spectroscopic analyses including 1D/2D NMR spectroscopy and HRESIMS. The absolute configuration was determined by modified Mosher's method. Compounds , and the mixture of and exhibited moderate cytotoxic activities against the human ovarian cancer cell line A2780 with IC values of 30.0 and 75.7 µM for and , respectively, in a nuclear shrinkage cytotoxicity assay.
Topics: Acetophenones; Benzopyrans; Cell Line, Tumor; Female; Hawaii; Humans; Magnetic Resonance Spectroscopy; Methylene Chloride; Ovarian Neoplasms; Plant Leaves; Rutaceae
PubMed: 33525713
DOI: 10.3390/molecules26030688 -
The Cochrane Database of Systematic... 2004Lymphoedema is the accumulation of excess fluid in the body caused by obstruction of the lymphatic drainage mechanisms. It can be caused by a number of factors,... (Review)
Review
BACKGROUND
Lymphoedema is the accumulation of excess fluid in the body caused by obstruction of the lymphatic drainage mechanisms. It can be caused by a number of factors, including congenital predisposition, parasitic infection or surgery. Lymphoedema is chronic and progressive and affects a significant proportion of the population. The standard treatment regimes include compression hosiery, skin care and exercise. The use of drugs in treatment, particularly benzo-pyrones, has gained favour over the last ten years. Benzo-pyrones, originally developed for use in vascular medicine, are prescribed to reduce vascular permeability and thus the amount of fluid forming in the subcutaneous tissues. Advocates for this treatment method believe that, as a result of reducing filtration, the drugs have some beneficial effect on pain and discomfort in the swollen areas. Proponents also claim that these drugs increase macrophage activity, encouraging the lysis of protein, which in turn reduces the formation of fibrotic tissue in the lymphoedematous limb.
OBJECTIVES
To assess the effectiveness of benzo-pyrones compared to placebo or to different benzo-pyrones in reducing limb volume, pain and discomfort in lymphoedematous limbs. To assess the effect of benzo-pyrones on the quality of affected tissues and on the patient's quality of life and, finally, to establish the incidence of adverse effects
SEARCH STRATEGY
We searched the Cochrane Breast Cancer Group register (September 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4,2003), MEDLINE, EMBASE, CINAHL, UnCover, PASCAL, SIGLE, reference lists produced by The British Lymphology Society, the National Research Register (NRR) and The International Society of Lymphology congress proceedings.
SELECTION CRITERIA
Types of studies considered for review were randomised controlled trials testing Paroven, coumarin, Venastat, Cyclo 3 Fort or Daflon versus placebo (with both groups having or not having standard physical treatment
DATA COLLECTION AND ANALYSIS
Eligibility for inclusion was confirmed by two blinded reviewers who screened the papers independently using a checklist of criteria relating to the randomisation and blinding of the trial. Both reviewers extracted data from the eligible studies using a data extraction form.
MAIN RESULTS
Overall, 15 trials were included that evaluated the role of benzo-pyrones. Three trials of oxerutin were found. Each tested the drug over 6 months using the same dose of drug against placebo. Two were crossover trials and one a parallel group trial with a total number of 127 participants and data available for only 81 of them. There were insufficient data provided in any of the trials to calculate the per cent reduction or increase in baseline excess limb volume. Standard deviations or confidence intervals and the numbers in the groups at the different stages of the trial were missing for all the data in two of the reports and for much of the data in the third, making any attempt at meta-analysis impossible. One trial testing Cyclo 3 Fort (approved name) over 3 months was found and involved 57 patients but provided insufficient data to allow a proper analysis of its findings. A single trial of Daflon (approved name) was found, lasting 6 months and involving 104 participants; once again there was insufficient information provided in the report to reach a conclusion about the effectiveness of the drug. Three trials of coumarin combined with troxerutin were found and tested two different doses of the drug against each other with no placebo, however, numbers of participants in the trial groups and baseline data were not provided. Eight trials of coumarin were identified. Two of the reports were confirmed as reporting the same trial and a further trial potentially also referred to the same trial but this was unconfirmed. A further two papers appeared to refer to the same trial but this was not confirmed. Three trials involved the same researcher. Five studies were conducted in India or China and they added anti-filarial dia or China and they added anti-filarial drugs to the interventions tested. The numbers of participants withdrawn and the numbers included in the analyses in all these trials were not extractable; the reporting of outcome measures in most of the trials was not clear. Loprinzi's 1999 trial in the USA reported the conduct of the trial and its findings with more detail, however, its conclusions were very much at odds with the findings of the other trials, finding that no difference was observed between those on the active preparation (coumarin) and placebo in any of the outcomes under investigation. This trial also reported a case of hepato-toxicity in a patient receiving the active preparation.
REVIEWERS' CONCLUSIONS
Meta-analysis was not performed due to the poor quality of the trials. It is not possible to draw conclusions about the effectiveness of Benzopyrones in reducing limb volume, pain, or discomfort in lymphoedematous limbs from these trials.
Topics: Anticoagulants; Benzopyrans; Coumarins; Diosmin; Extremities; Humans; Hydroxyethylrutoside; Lymphedema; Plant Extracts; Randomized Controlled Trials as Topic
PubMed: 15106192
DOI: 10.1002/14651858.CD003140.pub2 -
Journal of Medicinal Chemistry Apr 2020Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical...
Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Benzopyrans; Cell Line, Tumor; Crystallography, X-Ray; Cytochrome P-450 CYP3A; Gene Expression; Humans; Liver; Male; Mice, Inbred C57BL; Pregnane X Receptor
PubMed: 32160459
DOI: 10.1021/acs.jmedchem.0c00012 -
Bioorganic & Medicinal Chemistry Letters Jul 2024We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have...
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Topics: Metabolic Syndrome; Quinolines; Structure-Activity Relationship; Humans; Peroxisome Proliferator-Activated Receptors; Molecular Structure; Lipopolysaccharides; Anti-Inflammatory Agents; Macrophages; Dose-Response Relationship, Drug; Benzopyrans; Animals; Mice
PubMed: 38677560
DOI: 10.1016/j.bmcl.2024.129770 -
Angewandte Chemie (International Ed. in... Feb 2022Exciton coupling between two or more chromophores in a specific environment is a key mechanism associated with color tuning and modulation of absorption energies. This...
Exciton coupling between two or more chromophores in a specific environment is a key mechanism associated with color tuning and modulation of absorption energies. This concept is well exemplified by natural photosynthetic proteins, and can also be achieved in synthetic nucleic acid nanostructures. Here we report the coupling of barbituric acid merocyanine (BAM) nucleoside analogues and show that exciton coupling can be tuned by the double helix conformation. BAM is a nucleobase mimic that was incorporated in the phosphodiester backbone of RNA, DNA and GNA oligonucleotides. Duplexes with different backbone constitutions and geometries afforded different mutual dye arrangements, leading to distinct optical signatures due to competing modes of chromophore organization via electrostatic, dipolar, π-π-stacking and hydrogen-bonding interactions. The realized supramolecular motifs include hydrogen-bonded BAM-adenine base pairs and antiparallel as well as rotationally stacked BAM dimer aggregates with distinct absorption, CD and fluorescence properties.
Topics: Benzopyrans; DNA; Glycols; Indoles; Nucleic Acid Conformation; Nucleosides; RNA
PubMed: 34937127
DOI: 10.1002/anie.202116783