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7-(2-Oxoalkoxy)coumarins: Synthesis and Anti-Inflammatory Activity of a Series of Substituted Coumarins
Abstract
A series of 7-(2-oxoalkoxy)coumarins have been synthesized by conjugating substituted 7-hydroxycoumarins with different chloroketones. The anti-inflammatory properties of 7-(2-oxoalkoxy)coumarins were studied in LPS-induced inflammatory response in J774 macrophages. Western blot was used to determine the expression of iNOS and COX-2, NO was determined by measuring its metabolite nitrite by Griess reaction and IL-6 was measured by ELISA. Seventeen of the studied compounds inhibited NO and IL-6 production over 50% at 100 μM concentrations. IC50 values of the best inhibitors were 21 μM/24 μM (NO/IL-6) for compound 12 and 30 μM/10 μM (NO/IL-6) for compound 20. The main result was that the substitution with 7-(2-oxoalkoxy) group improved the anti-inflammatory properties of most of the investigated 7-hydroxycoumarins.
... 5-Farnesyloxycoumarin 36 showed the most potent activity against soybean lipoxygenase and 6-farnesyloxycoumarin 37 against human lipoxygenase. A great number of 7(2-oxoalkoxy)coumarins 38 have been prepared by condensation of hydroxycoumarins with α-chloroacetone [48] and the effects on expression of iNOS and COX-2 measured in comparison with 7-hydroxycoumarin. Result was that the substitution increased the activity compared to the unsubstituted one. ...
... Farnesyloxycoumarin 36 showed the most potent activity against soybean lipoxygenase oxoalkoxy)coumarins 38 have been prepared by condensation of hydroxycoumarins with α-chloroacetone[48] and the effects on expression of iNOS and COX-2 measured in comparison with ...
In this review, we will present the different aspects of coumarins and derivatives, fro natural origins or synthetically prepared, and their action on inflammation. Coumarins an also furo-And pyranocoumarins are found in many different plants. These compounds are ver often investigated for antioxidant properties. Other biological properties are also possible an anti-inflammation activity is one of these. As coumarins are also available quite easily via synthesis natural ones can be prepared this way but derivatives with special substituents are also feasible A review on the same topic appeared in 2004 and our contribution will take into account everythin published since then.
Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.
A chiral dirhodium complex is an effective and robust catalyst for asymmetric carbene transformations. However, dirhodium-catalyzed asymmetric ylide interception processes are rare, mainly because of the dissociation of the metal catalyst before the stereo-determining step. Herein, we report a chiral dirhodium(II)-catalyzed asymmetric annulation of vinyl diazoesters with α-hydroxyl ketones, which provides an efficient way to form chiral 2,3-dihydropyrans in good yields with excellent diastereos-electivities and enantioselectivities. This article is the first example of the chiral dirhodium complex—controlled asymmetric aldol-type interception of an in situ—formed oxonium ylide. The origin of the high stereoselectivity is well expounded via experimental and computational studies. These generated chiral products exhibit potent antiproliferation activity in three tested cancer cell lines, namely HCT116 (colon cancer), A549 (lung adenocarcinoma), and SJSA-1 (osteosarcoma cancer).
As a continuum to our work with coumarins, 12 psoralens were synthesized and evaluated for their anti‐inflammatory activity. Psoralens were prepared in three steps; at first, 7‐hydroxycoumarins were synthesized by von Pechmann condensation and then converted to 7‐(2‐oxopropoxy)coumarins. In the final step, a fused furan ring was introduced in an intramolecular ring‐formation reaction. Based on a SciFinder search, two out of the 12 synthesized psoralen derivatives (compounds 9 and 12) were found to be novel. The derivatives displayed anti‐inflammatory activity by suppressing iNOS and IL‐6 expression, but their mechanism of action seemed to be dependent on the substitution. Compound 6 with propyl side chain inhibited NF‐κB mediated transcription, while compound 10 with a phenyl substituent down‐regulated iNOS expression in a posttranscriptional manner. The results introduce psoralen derivatives as promising anti‐inflammatory compounds with potential for treatment of conditions involving iNOS and/or IL‐6‐mediated adverse responses.
Significant interest in the thieno[2,3-b]pyridine nucleus has arisen during the last three decades. Many researchers have reported the use of compounds based on this scaffold as a possible treatment of anxiety and depression, bacterial infection, inflammation, leishmaniasis, malaria and autoimmune diseases. Ortho-amino acyl thiophenes are possible starting material allowing to reach the thienopyridine structure. Access to these compounds was our first task for this thesis. We report here the first synthesis of 3-acetyl-2-aminothiophene by using the three-component Gewald reaction. These compounds exhibit a different mode of cyclisation in the reaction with Vilsmeier–Haack reagent than that reported for the reaction with o-aminoacetophenone, which could be ascribed to the influence of the thiophene nucleus. This simple, two-step reaction allows the construction of some novel 4-chlorothieno[2,3-b]pyridine derivatives from very simple building unit while which reacted further with aniline by palladium-catalysed C–N cross-coupling to give the coupled product in moderate to high yield. On other hand, 4-chloro-3-formylthieno[2,3-b]pyridine derivatives were synthesized by reaction between protected 3-acetyl-2-aminothiophenes and vilsmeier-Haack reagent under normal conditions. These products were not accessible neither without N-protection of the starting materials nor by reaction between the reagent and 4-chlorothieno [2,3-b]pyridine under any condition. Some derivatives of 4-methylthieno[2,3-b]pyridine were prepared by reaction between 3-acetyl-2-aminothiophene and some ketones under Friedländer condition
The discovery of COX enzymes has led to a better understanding of inflammation and its related biological pathways. Apart from being related to inflammation and pain, it has also been associated with cancer and neuropsychiatric diseases such as schizophrenia. Proverbially speaking, study of these enzymes has been crucial as they happen to "have fingers in many pies". Non-steroidal anti-inflammatory drugs (NSAID) that act specifically as COX-2 inhibitors have been known for a while; however these are also associated with severe side effects such as cardiac problems. Several heterocylic molecules have been tested for their anti-inflammatory activity specifically as COX-inhibitors. Coumarins also known as benzopyrans are widely found in nature, and are routinely employed as herbal remedies since early days. Over 1300 coumarins have been identified, principally as secondary metabolites in green plants, fungi and bacteria. Recently the use of natural and synthetic coumarins has garnered a lot of attention for their anti-inflammatory activities. In this review we delve further into the study of natural and synthetic coumarins as COX-inhibitors. Although the study is still in its nascent stage, we believe there is scope for a lot of development.
An efficient and convenient synthesis of highly functionalized dihydropyrans has been achieved through rhodium(i)-catalysed tandem C(sp³)-C(sp³) bond cleavage and annulation of oxetanols with alkynes. An enantioselective version was enabled using a Binaphine ligand. Excellent site-selectivity and remarkable enantioretention are obtained for 2-substituted oxetanols.
An eco-friendly one-pot procedure has been developed for the preparation of novel 2-oxochromene and benzofuran derivatives through the sequential addition/intramolecular cyclization reactions of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone, activated acetylenic compounds, and triphenylphosphine in the presence of catalytic amount of potassium fluoride impregnated clinoptilolite nanocatalyst in water at room temperature. The antioxidant activities of the newly synthesized derivatives (4a, 4b, and 5a) were also screened by diphenyl-2-picrylhydrazyl radical scavenging and ferric ion reducing potential assays compared with the synthetic antioxidants (2-tert-butylhydroquinone and butylated hydroxytoluene). Compounds 4a and 4b were shown good antioxidant activities.
Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
In inflammation, pro-inflammatory cytokines and bacterial products induce the production of high amounts of NO by inducible nitric oxide synthase (iNOS) in inflammatory and tissue cells. NO is an effector molecule in innate immunity, and it also has regulatory and pro-inflammatory/destructive effects in the inflammatory process. Protein kinase Cδ (PKCδ) is an important signaling protein regulating B lymphocyte functions, but less is known about its effects in innate immunity and inflammatory gene expression. In the present study we investigated the role of PKCδ in the regulation of iNOS expression in inflammatory conditions. NO production and iNOS expression were induced by LPS or a combination of cytokines IFNγ, IL-1β, and TNFα. Down-regulation of PKCδ by siRNA and inhibition of PKCδ by rottlerin suppressed NO production and iNOS expression in activated macrophages and fibroblasts. PKCδ directed siRNA and inhibition of PKCδ by rottlerin suppressed also the expression of transcription factor IRF1, possibly through inhibition of STAT1 activation. Accordingly, down-regulation of IRF1 by siRNA reduced iNOS expression in response to inflammatory stimuli. In addition, inhibition of PKCδ showed anti-inflammatory effects in carrageenan induced paw inflammation in mice as did iNOS inhibitor L-NIL. These results suggest that inhibitors of PKCδ have anti-inflammatory effects in disease states complicated by enhanced NO production through iNOS pathway.
5-Phenyl-7H-furo[2,3-g]chromen-7-ones and 9-phenyl-7H-furo-[2,3-f]chromen-7-ones, new analogs of psoralen and allopsoralen, are synthesized from 7-hydroxy- and 5-hydroxy-4-phenylcoumarins
New geiparvarin derivatives modified at the alkenyloxy bridge, where the 3′‐methyl group was replaced by a hydrogen atom, were synthesized and evaluated against a panel of human tumor cell lines in vitro. Compounds ( R )‐ 4 and ( R )‐ 5 show greater inhibitory activity toward cell growth than the parent geiparvarin. magnified image
New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3′‐methyl group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geiparvarin. The activity increased even further in the series of demethylated compounds, with the introduction of a methyl group at the 1′‐position of the alkenyloxy chain. In contrast, a remarkable decrease in activity was observed with the introduction of a methyl group at the 2′‐position. Interestingly, the new derivatives fully inhibited the growth of drug‐resistant cell lines, suggesting that they are not subject to pump‐mediated drug efflux. On the basis of their cytotoxic profiles, the most active compounds ( R )‐ 4 and ( R )‐ 5 were selected for further biological evaluation in comparison with the lead compound. The new derivatives strongly induce apoptosis in a promyelocytic leukemia cell line (HL‐60) mediated by depolarization of mitochondrial transmembrane potential and mitochondrial production of reactive oxygen species (ROS).
Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
A new automated system for the analysis of nitrate via reduction with a high-pressure cadmium column is described. Samples of urine, saliva, deproteinized plasma, gastric juice, and milk can be analyzed for nitrate, nitrite, or both with a lower limit of detection of 1.0 nmol NO3− or NO2−/ml. The system allows quantitative reduction of nitrate and automatically eliminates interference from other compounds normally present in urine and other biological fluids. Analysis rate is 30 samples per hour, with preparation for most samples limited to simple dilution with distilled water. The application of gas chromatography/mass spectrometry for the analysis of 15NO3− in urine after derivatization to 15NO2-benzene is also described.
Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer s, Parkinson s and AIDS dementia) neurodegenerative diseases, convulsions and pain; overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases; in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention. In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-amino acid-based inhibitors.
Nitric oxide (NO) is a key physiological mediator, and the association of disordered NO generation with many pathological conditions has led to much interest in pharmacologically modulating NO levels. However, the wide range of processes in which NO has been implicated, and the fact that increases or decreases in NO levels might be therapeutically desirable depending on the condition or even at different stages of the same condition, pose considerable challenges for drug development. Here, we focus on the rationale and potential for approaches that reduce NO synthesis, which have led to the development of several compounds that will shortly be entering clinical trials.
Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.
Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. It possesses cytotoxic properties that are aimed against pathogenic microbes, but it can also have damaging effects on host tissues. NO reacts with soluble guanylate cyclase to form cyclic guanosine monophosphate (cGMP), which mediates many of the effects of NO. NO can also interact with molecular oxygen and superoxide anion to produce reactive nitrogen species that can modify various cellular functions. These indirect effects of NO have a significant role in inflammation, where NO is produced in high amounts by inducible nitric oxide synthase (iNOS) and reactive oxygen species are synthesized by activated inflammatory cells. The present review deals with NO production and signaling in inflammation, especially in relation to human neutrophils and eosinophils.
Elevated levels of markers of nitric oxide (NO) production are found in osteoarthritic joints suggesting that NO is involved in the pathogenesis of osteoarthritis (OA). In OA, NO mediates many of the destructive effects of interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) in the cartilage, and inhibitors of NO synthesis have demonstrated retardation of clinical and histological signs and symptoms in experimentally induced OA and other forms of arthritis. As an important factor in cartilage, the regulation of inducible nitric oxide synthase (iNOS) expression and activity, and the effects of NO are reviewed, especially in relation to the pathogenesis of OA.
Inducible nitric oxide synthase (iNOS, also named NOSII or NOS2) is a high-output Ca ++-independent NOS whose expression can be induced in a wide range of cells and tissues by cytokines and other agents (for a review see ...
This chapter focuses on the physiological and pathological chemistry of nitric oxide. Nitric oxide is a simple molecule, consisting of single oxygen bonded to one nitrogen atom. Mammalian cells were discovered to produce nitric oxide (NO) as a short-lived intercellular messenger. The physiological implications continue to rapidly expand and have so far implicated nitric oxide in the regulation of blood pressure, platelet adhesion, neutrophil aggregation, as well as synaptic plasticity in brain. Nitric oxide and its secondary oxidants are also major cytotoxic agents produced by activated macrophages and neutrophils. This chapter begins with a discussion on why does nitric oxide have an unpaired electron. The chapter also discusses why half-life of nitric oxide is so short in vivo. It further explains concepts related to chemistry of nitric oxide and related nitrogen oxides. The chapter also describes handling and detection of nitric oxide. An overview of pathological implications of tyrosine nitration is also presented in this chapter. The chapter elaborates, in detail, the reactions with trace metal contaminants. The chapter concludes with a discussion on the chemistry of nitric oxide reacting with superoxide.
Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory) although all these properties have not been evaluated systematically. In addition their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published from 1990 till 2008, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues such as biscoumarins and triscoumarins. Information is also highlighted concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR. All rights reserved -
1nterleukin-6 (IL-6) is known as a proinflammatory cytokine involved in immune response, inflammation, and hematopoiesis. Inhibitory effects of anti-inflammatory drugs on IL-6 bioactivity using IL-6-dependent hybridoma have been evaluated, Three out of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) showed IC50 values of less than 100 muM, which were in the order of oxyphenylbutazone hydrate (IC50=7.5 muM)> meclofenamic acid sodium salt (31.9 muM)> sulindac (74.9 muM). Steroidal anti-inflammatory drugs (SAIDs) exhibited significant inhibitory effects at 100 muM on the IL-6 bioactivity, and their inhibitory potencies were in the order of budesonide (IC50=2.2 muM)> hydrocortisone 21-hemisuccinate (6.7 muM), prednisolone (7.5 muM), betamethasone (10.9 muM)> dexamethasone (18.9 muM) and triamcinolone acetonide (24.1 muM). The results would provide an additional mechanism by which anti-inflammatory drugs display their anti-inflammatory and immunosuppressive effects at higher concentrations.
The ability of titanium(IV) chloride as a catalyst to promote the Pechmann condensation reaction with a range of phenols and β-keto esters is described.The reaction was carried out by addition of TiCl4 to a mixture of the phenol and the β-keto ester with thorough stirring in the absence of a solvent and represents an improvement on the classical Pechmann conditions. The yields of coumarins obtained via this novel protocol were significantly higher than those using the conventional method and the reaction duration was reduced to a few minutes or even a few seconds.
A series of 1,3,4-oxadiazolyl-quinazolin-4(3H)ones have been synthesized using known methods. All
the compounds have been established on basis of elemental analysis, IR and NMR spectral data. The in
vitro antimicrobial screening of the synthesized compounds were carried out against two gram-positive
bacteria (S. aureus, S. pyogenes), two gram-negative bacteria (E. coli, P. aeruginosa), and three fungal
species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. The compounds 7d,
7g, 7l, 7o, 7p, and 7r possessed pronounced antibacterial activity whereas compound 7p exhibited
promising antifungal activity.
New amino psoralen derivatives have been synthesized via bromination. Bromination of 3,5-substituted psoralens has been studied. The second position of the furan ring is more susceptible to bromination than the a-position of the chromen-2-one ring in psoralens. Hence, the target psoralenamines were synthesized starting with 3-bromo-7-hydroxy-4-methyl-chromen-2-one, which was condensed with different a-halo ketones and cyclized in ethanolic potassium hydroxide to get the desired 6-bromo psoralens, which were finally converted into psoralenamines.
For Abstract see ChemInform Abstract in Full Text.
Some new psoralen derivatives were synthesized and evaluated as inhibitors of NF-κB/DNA interaction, with the aim to investigate the structural determinants required to inhibit this interaction. Starting from molecular docking studies, several possible protein binding sites were proposed and several three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the docked poses of 29 (the most active psoralen in the series) as templates for alignment of the inhibitors. The selected best model was validated through the prediction of the activity of 17 novel compounds. All the experimental data agreed with the computational experiments, supporting the reliability of the computational approach. The hypothesis about the interaction with NF-κB was also supported by surface plasmon resonance based assays using compound 29. All the collected data allowed the identification of compound 29 as a potential candidate for the development of pharmaceutical strategies against the inflammatory phenotype of cystic fibrosis.
For the first time, three coumarins were isolated from the hexane extract of limes (Citrus aurantifolia) and purified by flash chromatography. The structures were identified by NMR (1D, 2D) and mass spectral analyses as 5-geranyloxy-7-methoxycoumarin, limettin, and isopimpinellin. These compounds inhibited human colon cancer (SW-480) cell proliferation, with 5-geranyloxy-7-methoxycoumarin showing the highest inhibition activity (67 %) at 25 µM. Suppression of SW480 cell proliferation by 5-geranyloxy-7-methoxycoumarin was associated with induction of apoptosis, as evidenced by annexin V staining and DNA fragmentation. In addition, 5-geranyloxy-7-methoxycoumarin arrested cells at the G0/G1 phase, and induction of apoptosis was demonstrated through the activation of tumour suppressor gene p53, caspase8/3, regulation of Bcl2, and inhibition of p38 MAPK phosphorylation. These findings suggest that 5-geranyloxy-7-methoxycoumarin has potential as a cancer preventive agent.
Alkylation of umbelliferone and nitrophenol with chloroacetone, 3-chlorobutanone, 2-chlorocyclopentanone and 2-chlorocyclohexanone gave the corresponding 2-coumaryloxy and 2-nitrophenoxy ketones. The 2-coumaryloxy ketones were used as fluorogenic substrates to detect Baeyer–Villiger monooxygenases activities of microbial cultures in high-throughput using microtiter plates. The 2-coumaryloxy ketones were oxidized by microorganisms producing Baeyer–Villiger monooxygenases (BVMO), releasing umbelliferone as a fluorescent signal. The substrates were also biotransformed by a microbial monooxygenase (Trichosporon cutaneum). Chemical Baeyer–Villiger oxidation of 2-coumaryloxy ketones using meta-chloroperbenzoic acid proceeded regioselectively to the corresponding acyloxyalkyl derivatives of umbelliferone and nitrophenol. These chiral lactones underwent a fluorogenic and chromogenic reaction upon hydrolysis by esterases, in particular pig liver esterase. Enantioselectivity of the ester hydrolysis reaction was determined by chiral-phase analysis of the unreacted lactones.
A comparative study of application high-speed counter-current chromatography (HSCCC), and reversed-phase semi-preparative liquid chromatography (RPLC) for separating chemical compounds from Spiranthes australis (R. Brown) Lindl roots was investigated. Some parameters such as solvent system, flow rate of the mobile phase, separation time, solvent consuming, sample size, yields, recoveries and purities of the products were all investigated. The results indicated that three compounds were separated by HSCCC only in one run and less than 240 min with the purities and recoveries of over 97 and 91%, respectively, which were also isolated by RPLC with the purities of over 98.5% and recoveries of less than 75% using multiple chromatographic steps, and the total separation time and solvent consuming were about 7 and 13 times more than HSCCC. The obtained compounds were elucidated as 5-hydroxyl-7,4′-dimethoxy-flavone (1), 5-hydroxyl-7,3′,4′-dimethoxy-flavone (2), and 5-γ,γ-dimethylallyl-8-[2-(2,6-dihydroxyphenyl)-3-dimethyl-but-2-enyol]-umbelliferon (3), a novel compound, based on spectroscopic analysis.
A number of 7-hydroxycoumarins have been synthesised by Pechmann cyclisation using differently substituted resorcinols employing perchloric acid as the condensing agent. All the compounds have been characterised by analytical and spectroscopic methods. The anti-inflammatory properties were tested with LPS-induced inflammation in J774 macrophages. Expression of iNOS and COX-2 was determined by Western blot, NO by nitrite assay and IL-6 by ELISA analyses. Fifteen of the tested 7-hydroxycoumarins also inhibited IL-6 production but none of them had any major inhibitory effect on COX-2 expression.
Neuroinflammation and the activation of inducible nitric oxide synthase (iNOS) have been proposed to play a role in the pathogenesis of Parkinson disease (PD). In this study we investigated the effects of the selective iNOS inhibitor GW274150 in the 6-OHDA model of PD. 6-OHDA administration was associated with increased numbers of cells expressing iNOS. Administration of the iNOS inhibitor twice daily for 7 days, beginning 2 days after the 6-OHDA lesioning, led to a significant neuroprotection as shown by assessment of the integrity of the nigrostriatal system by tyrosine hydroxylase immunocytochemistry and HPLC assessment of striatal dopamine content. However, GW274150 displayed a bell-shaped neuroprotective profile, being ineffective at high doses. 6-OHDA lesioning was associated with an increase in microglial activation as assessed by the MHC II antigen OX-6 and the number of matrix metalloproteinase 9 (MMP-9)-immunopositive cells. NO is a known modulator of MMP-9, and iNOS inhibition was associated with decreased numbers of MMP-9-immunopositive cells, culminating in a reduction in the numbers of reactive microglia. Withdrawal of GW274150 for a further 7 days negated any neuroprotective effects of iNOS inhibition, suggesting that the damaging effects of inflammation last beyond 7 days in this model and the continued administration of the drug may be required.
Psoralen (1a) was found to be a specific and potent antimicrobial lead against Helicobacter pylori (H. pylori) from a traditional Chinese medicine (TCM) in the bioassay directed isolation. A series of structurally diverse analogues of 1a were thus designed and synthesized to improve the antimicrobial potency, some of which showed more potent activities than the lead compound (1a) against H. pylori. Among them, compound 25a is 16-fold stronger (MIC = 0.39 μg/mL) than 1a (MIC = 6.25 μg/mL), and is even potent than the positive control metronidazole (MIC = 0.50 μg/mL). The in vitro antimicrobial activities against H. pylori of these structurally diverse analogues based on the scaffold of 1a have also led to an outline of structure-activity relationship.
The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS) during sepsis leads to elevated NO levels that influence renal hemodynamics and cause peroxynitrite-related tubular injury through the local generation of reactive nitrogen species. In many organs iNOS is not constitutively expressed; however, it is constitutively expressed in the kidney and, in humans, a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated. For these reasons, the selective inhibition of renal iNOS might have important implications for the treatment of sepsis-induced AKI. Various animal studies have demonstrated that selective iNOS inhibition-in contrast to nonselective NOS inhibition-attenuates sepsis-induced renal dysfunction and improves survival, a finding that warrants investigation in clinical trials. In this Review, the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI is discussed.
N-(3-(Aminomethyl)benzyl)acetamidine (1400W) was a slow, tight binding inhibitor of human inducible nitric- oxide synthase (iNOS). The slow onset of inhibition by 1400W showed saturation kinetics with a maximal rate constant of 0.028 s-1 and a binding constant of 2.0 microM. Inhibition was dependent on the cofactor NADPH. L-Arginine was a competitive inhibitor of 1400W binding with a Ks value of 3.0 microM. Inhibited enzyme did not recover activity after 2 h. Thus, 1400W was either an irreversible inhibitor or an extremely slowly reversible inhibitor of human iNOS with a Kd value </= 7 nM. In contrast, inhibition of human neuronal NOS and endothelial NOS (eNOS) was relatively weaker, rapidly reversible, and competitive with L-arginine, with Ki values of 2 microM and 50 microM, respectively. Thus, 1400W was at least 5000-fold selective for iNOS versus eNOS. This selectivity was similar to that observed in rat aortic rings, in which 1400W was greater than 1000-fold more potent against rat iNOS than eNOS. Finally, 1400W was greater than 50-fold more potent against iNOS than eNOS in a rat model of endotoxin-induced vascular injury. Thus, the potency and selectivity of 1400W inhibition of iNOS both in vitro and in vivo were far greater than of any previously described iNOS inhibitor.
Interleukin-6 (IL-6) is known as a proinflammatory cytokine involved in immune response, inflammation, and hematopoiesis. Inhibitory effects of anti-inflammatory drugs on IL-6 bioactivity using IL-6-dependent hybridoma have been evaluated. Three out of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) showed IC50 values of less than 100 microM, which were in the order of oxyphenylbutazone hydrate (IC50=7.5 microM)>meclofenamic acid sodium salt (31.9 microM)>sulindac (74.9 microM). Steroidal anti-inflammatory drugs (SAIDs) exhibited significant inhibitory effects at 100 microM on the IL-6 bioactivity, and their inhibitory potencies were in the order of budesonide (IC50=2.2 microM)>hydrocortisone 21-hemisuccinate (6.7 microM), prednisolone (7.5 microM), betamethasone (10.9 microM)>dexamethasone (18.9 microM) and triamcinolone acetonide (24.1 microM). The results would provide an additional mechanism by which anti-inflammatory drugs display their anti-inflammatory and immunosuppressive effects at higher concentrations.
A series of 3-alkyl- and 3-aryl-7H-furo[3, 2-g]-1-benzopyran-7-ones, known as linear furocoumarins, was synthesized and evaluated for their dark- and photobinding (crosslink formation) with DNA as well as for their spectrophotometric and fluorescent properties, lipophilicity, and ability to photobleach N, N-dimethyl-p-nitrosoaniline (RNO) after irradiation with UVA light. 8-Methoxypsoralen (8-MOP, 9-methoxy-7H-furo[3, 2-g]-1-benzopyran-7-one) and 4, 5', 8-trimethylpsoralen (TMP, 2, 5, 9-trimethyl-7H-furo[3, 2-g]-1-benzopyran-7-one) were used as reference compounds in all tests. The investigations support the formation of a molecular complex between the furocoumarins and DNA. Crosslink formation with DNA after irradiation with UVA light was detectable for compounds with a methyl or phenyl substituent in position 3, but not for those bearing either a tert-butyl, a 4-methoxyphenyl, or a 2, 5-dimethoxyphenyl group. All furocoumarins exhibited sufficient absorption in the UVA wavelength range and are fluorescent. All compounds showed a higher lipophilicity than 8-MOP. Generally the 3-alkyl substituted furocoumarins had a capacity to photobleach RNOwhich was higher than that of the 3-aryl substituted ones. Some of the 3-aryl substituted furocoumarins displayed a photobleaching ability which was similar to or lower than that of 8-MOP.
The role of nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) is very complex. Induction of iNOS expression and hence NO production has been described to have beneficial antiviral, antiparasital, microbicidal, immunomodulatory, and antitumoral effects. However, induced at the wrong place or at the wrong time, iNOS has detrimental consequences and seems to be involved in the pathophysiology of different human diseases. The pathways regulating iNOS expression seem to vary in different cells or different species. In general, activation of the transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription (STAT)-1alpha and thereby activation of the iNOS promoter seems to be an essential step in the regulation of iNOS expression in most cells. Also, post-transcriptional mechanisms are critically involved in the regulation of iNOS expression.
Four new sesquiterpene coumarin derivatives, fukanemarin B (1), fukanefuromarin E (2), fukanefuromarin F (3) and fukanefuromarin G (5) were isolated from a 80% aqueous methanol extract of the roots of Ferula fukanensis. The structures were elucidated based on spectral evidence, especially heteronuclear multiple-bond connectivity (HMBC) and high-resolution MS. The 80% aqueous methanol extract of the roots of Ferula fukanensis (FFE) and the sesquiterpene coumarin derivatives inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) gene expression by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide (LPS) and recombinant mouse interferon-gamma (IFN-gamma).
Three naturally occurring isocoumarins (paepalantine, paepalantine 9-O-beta-D-glucopyranoside and paepalantine 9-O-beta-D-allopyranosyl(1 --> 6) glucopyranoside) and two semi-synthetic analogues, 9,10-acylated compound and 9-OH-10-methylated compound, structurally similar to paepalantine, were evaluated for antimicrobial activity using a spectrophotometric microdilution technique. The paepalantine was active against S. aureus, S. epidermidis, and E. faecalis while the other four compounds proved ineffective against all microorganisms tested at concentrations of 500 microg/ml. Variations in phenolic substitution at OH-9 and/or OH-10 in the paepalantine molecule resulted in compounds without antimicrobial activity. A combination of structural features, two phenolic groups as cathecolic system, forms an oxygenated system arrangement that may reflect the potentially antimicrobial properties of paepalantine.
Three series of functionalized coumarin compounds were designed and prepared as cholinesterase (AChE and BuChE) inhibitors. The biological profile against AChE and BuChE of the prepared compounds was determined. Compound 7b exhibited a mixed-type of AChE inhibitor with IC50 value for the AChE inhibition of 0.19+/-0.01 microM and a high selectivity for AChE/BuChE, and compound 6b acted as non-competitive AChE inhibitor with IC50 value of 0.43+/-0.02 microM. Structure-activity relationships (SARs) of prepared compounds were discussed.
The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.
The Ruta graveolens L. plant is used in traditional medicine to treat a large number of diseases. The methanol (50%) extract of the whole plant was observed to inhibit the expression of inducible nitric oxide synthase (iNOS) and the cycloxygenase-2 (COX-2) gene in lipopolysaccharide (LPS)-induced macrophage cells (J774A.1, [Raghav, S.K., Gupta, B., Agrawal, C., Goswami, K., Das, H.R., 2006b. Anti-inflammatory effect of Ruta graveolens L. in murine macrophage cells. J. Ethnopharmacol. 104, 234-239]). The effect of whole plant extract on the expression of other pro-inflammatory genes such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-12, interferon-gamma (IFN-gamma) and the activation of nuclear factor-kB (NF-kappaB) were investigated in LPS stimulated macrophage cells. An active compound was isolated from this methanol extract by further solvent fractionation and reverse phase high performance liquid chromatography (RP-HPLC). The purified compound was identified as 3-(1'-1'-dimethyl-allyl)-6-hydroxy-7-methoxy-coumarin having IUPAC nomenclature of 6-hydroxy-7-methoxy-3-(2-methyl but-3-en-2yl)-2H-chromen-2-one by ESI-MS, MALDI, FT-IR and NMR. Effect of this purified compound was assessed on iNOS, COX-2 and various pro-inflammatory cytokine genes and was observed to inhibit both the protein and mRNA expression of iNOS and IL-1beta in LPS challenged macrophages. Electrophoretic mobility shift assay (EMSA) and Western blot analyses indicated that the plant extract and the isolated active compound blocked the LPS-induced activation of NF-kappaB through the prevention of inhibitor-kB (IkB) degradation. The purified compound also showed the anti-oxidant activity. The active compound at a dose of 40 mg/kg body weight was observed to inhibit the iNOS and IL-1beta gene expression significantly in endotoxin-induced inflammatory model of BALB/c mice. The low level of nitric oxide production was also observed in the sera of compound treated mice. The normal behavioral condition in LPS challenged BALB/c mice was noticed when these were treated with active compound.
We have investigated the structure-activity relationship between 63 natural oxycoumarin derivatives and their effects on the expression of inducible-nitric oxide synthase (iNOS) induced by lipopolysaccharide. The protein expression of iNOS was screened by Western blot analysis, and four 5,7-dimethoxycoumarins were selected as potent inhibitors of iNOS expression. In terms of structural specificity, the methoxyl group on C-5 and C-7 and the short alkyl chain (1-5 carbons) on C-6 may be essential for the potent activities. These compounds also showed inhibitory effects on nitric oxide generation and mRNA expression of inflammatory mediators, namely, iNOS and COX-2. Interestingly, the inhibitory effect on mRNA expression was specific for iNOS and was not detected for neuronal NOS. It is expected that these compounds will show anti-inflammatory activities via inhibition of the expressions of iNOS and COX-2.
- L Zhang
- M Li
- L Wang
- J Gao
- C Ma
Zhang, L.; Li, M.; Wang, L.; Gao, J.; Ma, C. Can Chem Trans
2013, 1, 157.
[7] Motai, T., Kitanaka, S. Chem Pharm Bull (Tokyo) 2004, 52, 1215.
- B Zhang
- C Fan
- L Dong
- F Wang
- J Yue
Zhang, B.; Fan, C.; Dong, L.; Wang, F.; Yue, J. Eur J Med
Chem 2010, 45, 5258.
- H Kleinert
- A Pautz
- K Linker
- P M Schwarz
- P Vallance
- J Leiper
- S Heemskerk
- R Masereeuw
- F G Russel
- P Pickkers
- E Moilanen
- P H Aulaskari
Kleinert, H.; Pautz, A.; Linker, K.; Schwarz, P. M. Eur J
Pharmacol 2004, 500, 255.
[20] Vallance, P., Leiper, J. Nat Rev Drug Discov 2002, 1, 939.
[21] Heemskerk, S.; Masereeuw, R.; Russel, F. G.; Pickkers, P. Nat
Rev Nephrol 2009, 5, 629.
[22] Broom, L.; Marinova-Mutafchieva, L.; Sadeghian, M.; Davis, J. B.;
Medhurst, A. D.; Dexter, D. T. Free Radic Biol Med 2011, 50, 633.
[23] Timonen, J. M.; Nieminen, R. M.; Sareila, O.; Goulas, A.;
Moilanen, L. J.; Haukka, M.; Vainiotalo, P.; Moilanen, E.; Aulaskari, P. H.
HRMS (ESI-FTICR) Calcd for C 16 H 19 O 4 (M+H + ): 275.1278; found, 275.1278; Anal
- Oxoalkoxy
Oxoalkoxy)coumarins: Synthesis and Anti-Inflammatory Activity of a Series of
Substituted Coumarins
19.42, 20.64, 21.76, 26.73, 73.56, 108.17, 109.37, 111.19,
126.47, 141.34, 147.13, 153.74, 155.44, 161.37, 203.24; HRMS
(ESI-FTICR) Calcd for C 16 H 19 O 4 (M+H + ): 275.1278; found,
275.1278; Anal. Calcd for C 16 H 18 O 4 : C, 70.06, H 6.61: found:
C, 69.88; H, 6.56.
- J R Patil
- G K Jayaprakasha
- J Kim
- K N Murthy
- M B Chetti
- S Y Nam
- B S Patil
- Med
Patil, J. R.; Jayaprakasha, G. K.; Kim, J.; Murthy, K. N.;
Chetti, M. B.; Nam, S. Y.; Patil, B. S. Planta Med 2013, 79, 219.
[2] Peng, J.; Zhan, L.; Dong, F.; Han, X.; Qi, Y.; Xu, Y.; Xu, L.;
Xu, Q.; Liu, K. Sep Purif Technol 2008, 59, 262.
[3] Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E.
- F Borges
- F Roleira
- N Milhazes
- E Uriarte
Borges, F.; Roleira, F.; Milhazes, N.; Uriarte, E.; Santana, L.
Front Med Chem 2009, 4, 23.
Nitric Oxide: Principles and Actions
- J Lancaster
- Jr
- D J Stuehr
Lancaster, J., Jr.; Stuehr, D. J. Nitric Oxide: Principles and
Actions; Academic Press Inc.: USA, 1996; pp 148-164.
- J R Patil
- G K Jayaprakasha
- J Kim
- K N Murthy
- M B Chetti
- S Y Nam
- B S Patil
Patil, J. R.; Jayaprakasha, G. K.; Kim, J.; Murthy, K. N.;
Chetti, M. B.; Nam, S. Y.; Patil, B. S. Planta Med 2013, 79, 219.
- F Borges
- F Roleira
- N Milhazes
- E Uriarte
- L Santana
Borges, F.; Roleira, F.; Milhazes, N.; Uriarte, E.; Santana, L.
Front Med Chem 2009, 4, 23.
- L Zhang
- M Li
- L Wang
- J Gao
- C Ma
Zhang, L.; Li, M.; Wang, L.; Gao, J.; Ma, C. Can Chem Trans
2013, 1, 157.
- T Motai
- S Kitanaka
Motai, T., Kitanaka, S. Chem Pharm Bull (Tokyo) 2004, 52, 1215.