hymecromone and coumarin

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme upregulated in response to oxidative stress and in some cancers. Its upregulation by compounds has been used as an indicator of their potential anti-cancer properties. In this study we have designed, produced and tested a fluorogenic coumarin conjugate which selectively releases highly fluorescent 4-methylumbelliferone (4-MU) in the presence of NQO1. It was found that measuring 4-MU release rapidly and specifically quantitated NQO1 levels in vitro and in live cells. Both the substrate and its products freely perfused through cell membranes and were non-toxic. The substrate was very specific with low background, and the assay itself could be done in less than 10minutes. This is the first assay to allow the quantitation of NQO1 in live cells which can then be retained for further experiments.

Topics: Biomarkers; Cell Line, Tumor; Cell Membrane; Cell Membrane Permeability; Coumarins; Fluorescent Dyes; Humans; Hymecromone; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Oxidative Stress; Up-Regulation

A novel series of coumarin derivatives 6a-o, bearing isoxazole moieties were designed and synthesized. After that, they were evaluated for melanin synthesis in murine B16 cells and inhibitory effect on the growth of CA (Candida albicans), EC (Escherichia coli), SA (Staphylococcus aureus). It was found that eleven compounds (6b-f, 6j-o) showed a better activity on melanin synthesis than positive control (8-MOP). Among them, compounds 6d (242%) and 6f (390%), with nearly 1.6 and 2.6-fold potency compared with 8-MOP (149%) respectively, were recognized as the most promising candidate hits for further pharmacological study of anti-vitiligo. Seven halogen substituted compounds exhibited moderate antimicrobial activity against CA. It is interesting that 6e-f and 6l-m, which had two halogens on the benzene showed a comparable activity with Amphotericin B against CA. The evaluation of melanin synthesis in B16 cells and inhibitory effect on bacteria of above structurally diverse derivatives had also led to an outline of structure-activity relationship.

Topics: Anti-Bacterial Agents; Candida albicans; Cell Line, Tumor; Cell Survival; Coumarins; Dose-Response Relationship, Drug; Escherichia coli; Humans; Isoxazoles; Melanins; Microbial Sensitivity Tests; Molecular Structure; Staphylococcus aureus; Structure-Activity Relationship

Hymecromone is an important coumarin drug, and carprofen is one of the most important nonsteroidal antiinflammatory drugs (NSAIDs). The present study aims to determine the influence of bovine serum albumin (BSA) on the carprofen-hymecromone interaction. The inhibition of carprofen enantiomers on the UDP-glucuronosyltransferase (UGT) 2B7-catalyzed glucuronidation of hymecromone was investigated in the UGTs incubation system with and without BSA. The inhibition capability of increased by 20% (P < 0.001) of (R)-carprofen after the addition of 0.5% BSA in the incubation mixture. In contrast, no significant difference was observed for the inhibition of (S)-carprofen on UGT2B7 activity in the absence or presence of 0.5% BSA in the incubation system. The Lineweaver-Burk plot showed that the intersection point was located in the vertical axis, indicating the competitive inhibition of (R)-carprofen on UGT2B7 in the incubation system with BSA, which is consistent with the inhibition kinetic type of (R)-carprofen on UGT2B7 in the incubation system without BSA. Furthermore, the second plot using the slopes from the Lineweaver-Burk versus the concentrations of (R)-carprofen showed that the fitting equation was y=39.997x+50. Using this equation, the inhibition kinetic parameter was calculated to be 1.3 μM. For (S)-carprofen, the intersection point was located in the horizontal axis in the Lineweaver-Burk plot for the incubation system with BSA, indicating the noncompetitive inhibition of (S)-carprofen on the activity of UGT2B7. The fitting plot of the second plot was y=24.6x+180, and the inhibition kinetic parameter was 7.3 μM. In conclusion, the present study gives a short summary of BSA's influence on the carprofen enantiomers-hymecromone interaction, which will guide the clinical application of carprofen and hymecromone.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biocatalysis; Carbazoles; Coumarins; Glucuronosyltransferase; Hymecromone; Kinetics; Serum Albumin, Bovine; Stereoisomerism

Asthma is a chronic inflammatory disorder that causes contraction in the smooth muscle of the airway and blocking of airflow. Reversal the contractile process is a strategy for the search of new drugs that could be used for the treatment of asthma. This work reports the semisynthesis, ex vivo relaxing evaluation and SAR studies of a series of 18 coumarins. The results pointed that the ether derivatives 1-3, 7-9 and 13-15 showed the best activity (Emax = 100%), where compound 2 (42 μM) was the most potent, being 4-times more active than theophylline (positive control). The ether homologation (methyl, ethyl and propyl) in position 7 or positions 6 and 7 of coumarins lead to relaxing effect, meanwhile formation of esters generated less active compounds than ethers. The SAR analysis showed that it is necessary the presence of two small ether groups and the methyl group at position 4 (site 3) encourage biological activity through soft hydrophobic changes in the molecule, without drastically affecting the cLogP.

Topics: Animals; Anti-Asthmatic Agents; Coumarins; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Models, Molecular; Molecular Structure; Rats; Rats, Wistar; Structure-Activity Relationship; Trachea

Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a,b, 15, and 17a,b) were designed, synthesized, and evaluated against the A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines. Most derivatives displayed potent antiproliferation activities. Among them, 8b exhibited the strongest antiproliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem, and SKOV3/CDDP with IC50 values from 14 to 53 nM and from 62 to 140 nM, respectively. Furthermore, 8b inhibited the growth of A2780 in vivo and displayed lower toxicity on nontumorigenesis T29, showing good selectivity against malignant cells in vitro. Preliminary pharmacological studies showed that 8b induces apoptosis, arrests the cell cycle at the G2/M phase in the A2780 cell line, and disrupts the phosphorylation of MEK1 and ERK1. Overall, the NO-releasing capacity and the inhibition of ERK/MAPK pathway signaling may explain the potent antineoplastic activity of these compounds.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinogenesis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Combinations; Drug Screening Assays, Antitumor; Female; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Inhibitory Concentration 50; MAP Kinase Kinase 1; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 3; Neoplasms; Nitric Oxide; Oxadiazoles; Signal Transduction

Hydrogen sulfide (H2S) is an integral signaling molecule in biology with complex generation, translocation, and metabolism processes that are intertwined with cellular thiols. Differentiating the complex interplay between H2S and biological thiols, however, remains challenging due to the difficulty of monitoring H2S and thiol levels simultaneously in complex redox environments. As a step toward unraveling the complexities of H2S and thiols in sulfur redox homeostasis, we present a dual-fluorophore fragmentation strategy that allows for the ratiometric determination of relative H2S and cysteine (Cys) or homocysteine (Hcy) concentrations, two important metabolites in H2S biosynthesis. The key design principle is based on a nitrobenzofurazan-coumarin (NBD-Coum) construct, which fragments into spectroscopically differentiable products upon nucleophilic aromatic substitution with either H2S or Cys/Hcy. Measurement of the ratio of fluorescence intensities from coumarin and the NBD-Cys or NBD-Hcy adducts generates a sigmoidal response with a dynamic range of 3 orders of magnitude. The developed scaffold displays a rapid response (<1 min) and is selective for sulfhydryl-containing nucleophiles over other reactive sulfur, oxygen, and nitrogen species, including alcohol- and amine-functionalized amino acids, polyatomic anionic sulfur species, NO, and HNO. Additionally, NBD-Coum is demonstrated to differentiate and report on different oxidative stress stimuli in simulated sulfur pools containing H2S, Cys, and cystine.

Topics: 4-Chloro-7-nitrobenzofurazan; Chemistry Techniques, Analytical; Coumarins; Cysteine; Fluorescent Dyes; Homocysteine; Hydrogen Sulfide; Hymecromone; Oxadiazoles; Oxidation-Reduction; Spectrometry, Fluorescence

Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket-1 (TP-1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A- and B-rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC50 values between 17 and 63 μm. Of these, the newly synthesized 6,8-diallyl-5,7-dihydroxycoumarin (8a) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB-34. The binding site of 8a was mapped to TP-1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP-1 site binders. NS5B-TP-1-8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.

Topics: Anticoagulants; Antiviral Agents; Binding Sites; Coumarins; Drug Evaluation, Preclinical; Enzyme Inhibitors; Flavones; Hepacivirus; RNA-Dependent RNA Polymerase; Viral Nonstructural Proteins

A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced β-amyloid (Aβ) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 μM) and Aβ aggregation (67.8%, 20 μM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 μM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterases; Coumarins; Dose-Response Relationship, Drug; Drug Design; Electrophorus; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Tacrine

Photo-responsive monoolein (MO) cubic phase was developed by incorporating coumarin-Tween 20 conjugate in the cubic phase. 7-chlorocarbonylmethoxycoumarin was obtained from 7-hydroxycoumarin through three-step reactions with the yield of 19.8% and it was conjugated to the head group of Tween 20. The molar ratio of the coumarin derivative/Tween 20 in the conjugate was about 1/1 on ¹H NMR spectrum. The cubic phase was prepared by melting the mixture of MO/conjugate (100/0.88, w/w) and hydrating the molten mixture with 5(6)-carboxyfluorescein (CF) solution. UV irradiation (254 nm and/or 365 nm) for 3 h resulted in 1.27% to 2.69% reduction in the double bond of MO but the cubic phase was stable in terms of its integrity under the UV irradiation. The release of CF from coumarin-Tween 20 conjugate-incorporated cubic phase was somewhat suppressed by being subjected to the UV irradiation. The head groups of coumarin-Tween 20 conjugate will be cross-linked so the diffusion in the water channel will be suppressed.

Topics: Anticoagulants; Coumarins; Dimerization; Drug Delivery Systems; Drug Stability; Fluoresceins; Fluorescent Dyes; Glycerides; Hot Temperature; Hymecromone; Kinetics; Magnetic Resonance Spectroscopy; Pharmaceutical Vehicles; Phase Transition; Photochemical Processes; Polysorbates; Solubility; Surface-Active Agents; Ultraviolet Rays; Umbelliferones

A series of new coumarin-based 1,2,4-triazole derivatives were designed, synthesized and evaluated for their antimicrobial activities in vitro against four Gram-positive bacteria (Staphylococcus aureus, MRSA, Bacillus subtilis and Micrococcus luteus), four Gram-negative bacteria (Escherichia coli, Proteus vulgaris, Salmonella typhi and Shigella dysenteriae) as well as three fungi (Candida albicans, Saccharomyces cerevisiae and Aspergillus fumigatus) by two-fold serial dilution technique. The bioactive assay showed that some synthesized coumarin triazoles displayed comparable or even better antibacterial and antifungal efficacy in comparison with reference drugs Enoxacin, Chloromycin and Fluconazole. Coumarin bis-triazole compounds exhibited stronger antibacterial and antifungal efficiency than their corresponding mono-triazole derivatives.

Topics: Anti-Infective Agents; Coumarins; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Triazoles

The comparison of the antioxidant activity of some coumarins with their molecular structure is well determined. However, the protective function of coumarins with various chemical structures against liver toxicity has not yet been well established. Therefore, the aim of this study was to evaluate the possible cytoprotective properties of coumarin and some coumarin derivatives against CCl(4) (carbon tetrachloride)-induced hepatotoxicity. Coumarin (1,2-benzopyrone) and coumarin derivatives esculetin (6,7-dihydroxycoumarin), scoparone (6,7-dimethoxycoumarin) and 4-methylumbelliferone (7-hyroxy-4-methyl) were examined for their protective effect against CCl(4)-induced hepatotoxicity in Male Sprague-Dawley rats. A single toxic dose of CCl(4) (1.25 ml kg(-1), orally) produced liver damage in rats, seen histologically as centrilobular necrosis. Administration of CCl(4) increased serum enzyme levels of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP). Pre-treatment of rats with esculetin (31.15 mg kg(-1), orally) and scoparone (35 mg kg(-1), orally) significantly prevented CCl(4)-induced increase in serum enzymes, whereas 4-methylumbelliferone (35 mg kg(-1)) and coumarin (30 mg kg(-1)) had no effect against CCl(4)-induced rise in serum enzymes. Morphological findings were consistent with the plasma transaminase observations. Among the coumarin analogs, esculetin, which possesses orthodihydroxy coumarins, showed the strongest protective effect against CCl(4)-induced liver damage, followed by scoparone, 4-methylumbelliferone and coumarin, respectively. The results of this study indicate that the chemical structures of coumarins play an important role in the prevention of liver toxicity.

Topics: Animals; Antioxidants; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Coumarins; Hymecromone; Male; Rats; Rats, Sprague-Dawley; Umbelliferones

Four known coumarins, coumarin (1), 7-hydroxy-3-methylcoumarin (2), oreoselone (3) and heraclenin (4), were isolated from aerial part of Halocnemum strobilaceum. Their structures were determined by 1 and 2-D NMR techniques.

Topics: Chenopodiaceae; Coumarins; Furocoumarins; Humans; Hymecromone; Magnetic Resonance Spectroscopy; Plant Extracts; Plants, Medicinal

Zirconium complexes of mendiaxon, warfarin, coumachlor, and niffcoumar have been synthesized by reaction of the ligands with zirconium chloride in stoichiometric ratio 1:2. The formation of the complexes has been proved on the basis of elemental analysis, IR-spectroscopy, 1H-NMR spectroscopy, and thermal studies. Differential thermal analyses and thermogravimetric analyses have been applied to study the compositions of the new complexes. It is concluded that the lactone- and the keto-carbonyl groups of warfarin, coumachlor, and niffcoumar are bonded to the metal ion as bidentate ligands, but mendiaxon is bonded as monodentate ligand. Cytotoxic screening by MTT-assay was carried out. Among these compounds the zirconium complex of mendiaxon showed highest cytotoxic activity against human promyelocytic leukemic HL-60 cells. The inorganic salt was found to be active against this cell line.

Topics: Antineoplastic Agents; Cell Survival; Coumarins; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Hymecromone; Ligands; Magnetic Resonance Spectroscopy; Organometallic Compounds; Spectrophotometry, Infrared; Warfarin; Zirconium

Cerium complexes of Umbellipherone, Mendiaxon, Warfarin, Coumachlor, and Niffcoumar have been synthesized by reaction of the ligands with cerium nitrate in a stoichiometric ratio of 1:2. The formation of the complexes has been proved on the basis of elemental analysis, conductivities, IR spectroscopy, and 1H-NMR spectroscopy. The molecules of the ligands were optimized by means of the semiempirical quantum mechanical method PM3 to the energetically most stable conformers. All the ligands were characterized by molecular and submolecular electronic indices and the putative donor centers are proposed. It is concluded that the lactone- and the keto-carbonyl groups of Warfarin, Coumachlor, and Niffcoumar are bonded to the metal ion as bidentate ligands. The other two coumarins are bonded as monodentate ligands. Conductivity measurements show the non-electrolytic nature of the complexes. Cytotoxic screening by MTT assay was carried out. The cerium complexes were found to be more active than the inorganic salts.

Topics: 4-Hydroxycoumarins; Antineoplastic Agents; Cell Survival; Cerium; Coumarins; Humans; Hymecromone; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Organometallic Compounds; Spectrophotometry, Infrared; Tumor Cells, Cultured; Warfarin

Topics: Coumarins; Fluorometry; Glucuronidase; Glucuronides; Glycoside Hydrolases; Hymecromone; Umbelliferones