- Urolithin compound, preparation method, pharmaceutical composition and application
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The invention belongs to the field of medicinal chemistry, and particularly relates to a urolithin compound, a preparation method, a pharmaceutical composition and application. The urolithin compound is a compound as shown in a general formula I or an optical isomer, an enantiomer, a diastereomer, a raceme or a raceme mixture of the compound, or a pharmaceutically acceptable salt of the compound. The urolithin compound provided by the invention has good PDE2 inhibitory activity, the enzymatic level IC50 reaches 3.67 [mu] M, and the urolithin compound can be used for treating central nervous system diseases and brain neurodegenerative process diseases, and can be used as an active component to prepare drugs for inhibiting PDE2 activity.
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Paragraph 0112-0121
(2021/09/04)
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- Design, synthesis, and biological evaluation of novel 6h-benzo[c]chromen-6-one derivatives as potential phosphodiesterase ii inhibitors
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Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC50: 3.67 ± 0.47 μM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.
- Tang, Long,Jiang, Jianchun,Song, Guoqiang,Wang, Yajing,Zhuang, Ziheng,Tan, Ying,Xia, Yan,Huang, Xianfeng,Feng, Xiaoqing
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- Urolithin and reduced urolithin derivatives as potent inhibitors of tyrosinase and melanogenesis: Importance of the 4-substituted resorcinol moiety
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We previously reported (E)-β-phenyl-α,β-unsaturated carbonyl scaffold ((E)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosi-nase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyro-sinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (E)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds 1c (IC50 = 18.09 ± 0.25 μM), 1h (IC50 = 4.14 ± 0.10 μM), and 2a (IC50 = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC50 = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhi-bition.
- Lee, Sanggwon,Choi, Heejeong,Park, Yujin,Jung, Hee Jin,Ullah, Sultan,Choi, Inkyu,Kang, Dongwan,Park, Chaeun,Ryu, Il Young,Jeong, Yeongmu,Hwang, Yeji,Hong, Sojeong,Chun, Pusoon,Moon, Hyung Ryong
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- Urolithins as immune response enhancers
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Disclosed are compounds for use in raising an immune response to an antigen and/or enhancing, modulating or augmenting an immune response to an antigen. Particularly the use of urolithins. The invention also relates to immune enhancers comprising urolithins, methods of using such immune enhancers and processes for the preparation of such immune enhancers. The invention also relates to the use of urolithins in methods for modulating stem cell function, for example, enhancing stem cell numbers, promoting stem cell regeneration and promoting stem cell differentiation.
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Page/Page column 30-31
(2020/11/23)
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- Urolithin A and B Derivatives as ON-OFF Selective Fluorescent Sensors for Iron(III)
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The detection and sensing of environmentally crucial metal ions has always been of great significance in various fields such as biological and environmental cycles. Our previous studies have indicated a new coumarin based lactone, Urolithin B (i.e., 3-Hydroxy[c]chromen-6-one) as a potent fluorescent probe for the selective detection of Iron (III). In order to question the extension of this application to other urolithins, we have synthesized the major urolithins that humans are exposed to through regular diet. Following the structure identifying studies, the compounds were tested in fluorescence titration to investigate their interaction with various metals. The results have indicated that each title compound is selective to interact with Iron (III) in ON-OFF mode, independent from the presence of another metal. Similar to the previous findings, the Job’s plots displaying the ratio of complex formation 3:2 UROs:Fe3+ have indicated the significance of the lactone group solely.
- Fallah, Amirhossein,Noshadi, Bahareh,Gazi, Mustafa,Gülcan, Hayrettin Ozan
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p. 113 - 120
(2020/01/06)
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- Synthesis, Characterization, Molecular Docking, and Biological Activities of Some Natural and Synthetic Urolithin Analogs
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Urolithins (that is, hydroxy substituted benzo[c]chromen-6-one derivatives) are formed within the gastrointestinal tract following to the exposure to various ellagitannin rich diet, particularly involving pomegranate, nuts, and berries. Regarding the bioavailability deficiency of ellagitannins, the biological activities obtained through the extracts of these dietaries are attributed to the urolithin compounds, since they are bioavailable. Particularly, there are studies indicating the importance of ellagitannin-rich food for protective and alternative treatment of Alzheimer's Disease (AD). From this perspective, within this study, the major urolithins (that is, urolithins A and B), their methyl ether metabolites, as well as some synthetic urolithin analogs have been synthesized and screened for their biological activities in various enzyme inhibition (acetylcholinesterase, butyrylcholinesterase, monoamine oxidase B, cyclooxygenase 1, and cyclooxygenase 2) and antioxidant (DPPH radical scavenging) assay systems. The results pointed out the potential of urolithins to act as inhibitors on these receptors. Docking studies were also performed to investigate the possible interactions.
- Noshadi, Bahareh,Ercetin, Tugba,Luise, Chiara,Yuksel, Mine Yarim,Sippl, Wolfgang,Sahin, Mustafa Fethi,Gazi, Mustafa,Gulcan, Hayrettin Ozan
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- Comprehensive kinetic and substrate specificity analysis of an arylsulfatase from Helix pomatia using mass spectrometry
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Sulfatases hydrolyze sulfated metabolites to their corresponding alcohols and are present in all domains of life. These enzymes have found major application in metabolic investigation of drugs, doping control analysis and recently in metabolomics. Interest in sulfatases has increased due to a link between metabolic processes involving sulfated metabolites and pathophysiological conditions in humans. Herein, we present the first comprehensive substrate specificity and kinetic analysis of the most commonly used arylsulfatase extracted from the snail Helix pomatia. In the past, this enzyme has been used in the form of a crude mixture of enzymes, however, recently we have purified this sulfatase for a new application in metabolomics-driven discovery of sulfated metabolites. To evaluate the substrate specificity of this promiscuous sulfatase, we have synthesized a series of new sulfated metabolites of diverse structure and employed a mass spectrometric assay for kinetic substrate hydrolysis evaluation. Our analysis of the purified enzyme revealed that the sulfatase has a strong preference for metabolites with a bi- or tricyclic aromatic scaffold and to a lesser extent for monocyclic aromatic phenols. This metabolite library and mass spectrometric method can be applied for the characterization of other sulfatases from humans and gut microbiota to investigate their involvement in disease development.
- Correia, Mário S.P.,Ballet, Caroline,Meistermann, Hannes,Conway, Louis P.,Globisch, Daniel
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p. 955 - 962
(2019/02/09)
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- METHODS FOR IMPROVING MITOPHAGY IN SUBJECTS
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The invention provides a compound of formula (I) wherein: A, B, C, D, W, X, Y and Z are each independently selected from H and OH; or a salt thereof; for use in the treatment and/or prophylaxis of a condition, disease or disorderin a subject, wherein the compound or salt is orally administered to a subject in adaily amount of from 1.7 to 2.7 mmol per day, over a period of at least 21 days. Also are provided are the compound of formula (l) for use in increasing mitophagy and/or autophagy, maintaining and/or improving muscle function and administration as a dietary, nutritional and/or health supplement.
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Page/Page column 52
(2018/09/28)
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- METHODS FOR IMPROVING MITOPHAGY IN SUBJECTS
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The invention provides a compound of formula (I) wherein: A, B, C, D, W, X, Y and Z are each independently selected from H and OH; or a salt thereof; for use in the treatment and/or prophylaxis of a condition, disease or disorderin a subject, wherein the compound or salt is orally administered to a subject in a daily amount of from 2.8 to 6.6mmol per day, over a period of at least 21 days. Also are provided are the compound of formula (l) for use in increasing mitophagy and/or autophagy, maintaining and/or improving musclefunction and administration as a dietary, nutritional and/or health supplement.
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Page/Page column 54
(2018/09/28)
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- SKIN TREATMENT METHODS
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The invention provides a compound of formula (I) wherein: A, B, C, D, W, X, Y and Z are each independently selected from H and OH; or a salt thereof; for use in the treatment and/or prevention of a skin condition in a subject, wherein the compound of formula (I) or salt thereof is administered topically. The invention further provides topical compositons of a compound of formula (i) and processes for the preparation of said compositions.
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Page/Page column 29
(2018/09/28)
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- Urolithin C, a gut metabolite of ellagic acid, induces apoptosis in PC12 cells through a mitochondria-mediated pathway
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Urolithins (Uros), metabolites of ellagitannins (ET) and ellagic acid (EA) produced by gut microbiota, showed better bioavailability and extensive bioactivity, and were considered as the active compounds responsible for the health benefits exerted by ET-containing foodstuffs. Here, we chemically synthesized three Uros including Uros A, B, and C and compared their anti-proliferative activities with that of EA in PC12 cells. MTT assay showed that EA significantly promoted, while Uros significantly inhibited the proliferation of PC12 cells, among which UroC showed the strongest anti-proliferation. UroC treatment actively increased the lactate dehydrogenase (LDH) release and lipid peroxidation malondialdehyde (MDA), stimulated reactive oxygen species (ROS) formation and mitochondrial membrane depolarization, and caused calcium dyshomeostasis. Furthermore, flow cytometry analysis showed that UroC treatment induced apoptosis and S phase cell cycle arrest with increasing UroC concentrations. Consequently, UroC also induced imbalance in the Bcl-2/Bax ratio, which triggered the caspase cascade, thereby shifting the balance in favor of apoptosis, as evidenced by western blotting and real-time PCR. These observations indicated that UroC possessed significantly different anti-proliferation activities from EA, and actively induced cell apoptosis through a mitochondria-mediated pathway.
- Yin, Peipei,Zhang, Jianwei,Yan, Linlin,Yang, Lingguang,Sun, Liwei,Shi, Lingling,Ma, Chao,Liu, Yujun
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p. 17254 - 17263
(2017/03/27)
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- COMPOSITIONS COMPRISING AN UROLITHIN COMPOUND
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The invention provides compositions comprising a source of protein and a urolithin. The invention also provides uses and methods associated with, or making use of the compositions, such as a medicament, dietary supplement, functional food or medical food and in the treatment and/or prophylaxis of a muscle-related pathological condition. The invention also provides kits comprising urolithin and protein.
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Page/Page column 20
(2017/03/21)
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- COMPOSITIONS COMPRISING UROLITHIN COMPOUNDS
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The invention provides compositions comprising a medium chain triglyceride and a urolithin. The invention also provides uses and methods associated with, or making use of the compositions,such as a medicament, dietary supplement, functional food or medical food and in the treatment and/or prophylaxis of a muscle-related pathological condition.
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Page/Page column 21
(2017/03/21)
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- COMPOSITIONS COMPRISING NICOTINAMIDE RIBOSIDE AND A UROLITHIN
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A composition comprising: a)nicotinamide riboside and b)a urolithin which is a compound of formula (I) or a salt thereof: Formula (I) wherein: A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; and Z is selected from H and OH. The compositions are useful as medicaments, for example for treating muscle-related pathological conditions, neurodegenerative diseases, and/or mitochondrial diseases and as dietary supplements, functional foods and beverages, and specialised nutrition or medical foods.
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Page/Page column 25
(2017/07/14)
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- PROCESS-SCALE SYNTHESIS OF UROLITHINS
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Disclosed is a method of preparing a urolithin, or an intermediate or analog thereof, having a dibenzo[b,d]pyran-6-one core. The method is especially advantageous for the large-scale preparation of urolithins or intermediates or analogs thereof. The method may optionally include the preparation of a urolithin, or an intermediate or analog thereof, as a pharmaceutically acceptable salt.
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Page/Page column 38; 39; 40
(2015/07/15)
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- ENHANCING AUTOPHAGY OR INCREASING LONGEVITY BY ADMINISTRATION OF UROLITHINS OR PRECURSORS THEREOF
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Disclosed are methods, compounds, and compositions useful for increasing autophagy and promoting longevity. The methods, compounds, and compositions relate to urolithins and urolithin precursors and use thereof. Certain urolithins are represented by Formula I, while certain urolithin precursors are represented by Formula IV. The urolithin may be urolithin A, urolithin B, urolithin C, or urolithin D. The urolithin precursor may be ellagic acid or an ellagitannin. The methods include in vivo, ex vivo, and in vitro uses of the compounds and compositions.
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Page/Page column 223-224
(2014/01/17)
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- Urolithin as a Converging Scaffold Linking Ellagic acid and Coumarin Analogues: Design of Potent Protein Kinase CK2 Inhibitors
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Casein kinase2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (Ki=20nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, Ki=60nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithinA as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a Ki value of 7nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments. Two become one: Comparing the crystallographic binding modes of ellagic acid (red) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC; blue), an X-ray structure-driven merging approach to the design of novel casein kinase2 (CK2) inhibitors was taken. Using this strategy, a potent and selective urolithin derivative, 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one was identified, which exhibits a Ki value of 7nM against CK2.
- Cozza, Giorgio,Gianoncelli, Alessandra,Bonvini, Paolo,Zorzi, Elisa,Pasquale, Riccardo,Rosolen, Angelo,Pinna, Lorenzo A.,Meggio, Flavio,Zagotto, Giuseppe,Moro, Stefano
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p. 2273 - 2286
(2012/04/11)
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- Urolithins, intestinal microbial metabolites of pomegranate ~ellagitannins, exhibit potent antioxidant activity in a cell-based assay
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Many health benefits of pomegranate products have been attributed to the potent antioxidant action of their tannin components, mainly punicalagins and ellagic acid. While moving through the intestines, ellagitannins are metabolized by gut bacteria into urolithins that readily enter systemic circulation. In this study, the antioxidant properties of seven urolithin derivatives were evaluated in a cell-based assay. This method is biologically more relevant because it reflects bioavailability of the test compound to the cells, and the antioxidant action Is determined in the cellular environment. Our results showed that the antioxidant activity of urolithins was correlated with the number of hydroxy groups as well as the lipophilicity of the molecule. The most potent antioxidants are urolithins C and D with IC50 values of 0.16 and 0.33 μM, respectively, when compared to IC50 values of 1.1 and 1.4 μM of the parent ellagic acid and punicalagins, respectively. The dihydroxylated urolithin A showed weaker antioxidant activity, with an IC 50 value 13.6 μM, however, the potency was within the range of urolithin A plasma concentrations. Therefore, products of the intestinal microbial transformation of pomegranate ellagitannins may account for systemic antioxidant effects.
- Dobroslawa, Bialonska,Kasimsetty, Sashi G.,Khan, Shabana I.,Daneel, Ferreira
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experimental part
p. 10181 - 10186
(2010/07/18)
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- Mitochondria-targeted antioxidants
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The present invention relates to a pharmaceutical or veterinary or nutritional or personal care composition comprising coenzyme Q10 (CoQ10), reduced CoQ10, or mixtures thereof and oxygenated dibenzo-α-pyrone or an amino acyl ester thereof. The composition of the present invention is able to support and/or provide therapy to individuals at risk and/or under treatment for dysfunctions of energy metabolism, and specifically, for mitochondrial diseases.
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Page/Page column 6
(2008/06/13)
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- Compositions of stable bioactive metabolites of docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids
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An invention that adduces cogent evidence to establish that oxygenated dibenzo-α-pyrones (DBPs and their conjugates), the major bioactives of shilajit (Ayurvedic vitalizer), have their origin, at least partly, in EPA and DHA. Earlier research has shown that, in mammals, C-20 PUFAs are metabolized by oxygenases and other enzymes to produce short-lived prostaglandins, leukotrienes and thromboxanes that bind to specific G-protein-coupled receptors and signal cellular responses, e.g., inflammation, vasodilation, blood pressure, pain etc. But never before it was suggested/shown that C20:5n-3 (and C22:6 n-3) PUFAs, e.g., EPA (and DHA), are transformed into stable aromatic metabolites, DBPs, which elicit a large array of bioactivities in the producer organisms and also control the synthesis and metabolism of arachidonate-derived prostaglandins. The major beneficial effects attributed to EPA and DHA are now found to be largely contributed by DBPs and their aminoacyl conjugates and the dibenzo-α-pyrone-chromoproteins (DCPs). Because of the highly unstable nature of EPA and DHA, when administered, they are metabolized into a large array of uncontrolled products, several of which are systemically undesirable. By contrast, DBPs, because of their stability, perform the biological response modifier (BRM) functions in a directed and sustained way. Many of the biological effects of DBPs described in this invention, were earlier attributed to EPA and DHA,—the precursors of DBPs.
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Page/Page column 8-9
(2008/06/13)
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- Modified coumarins. 15. Condensed psoralen derivatives based on substituted dibenzo[b,d]pyran-6-ones
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Benzo[c]furo[3,2-g]chromen-5-ones, modified psoralen analogs containing a substituted benzene ring annelated at the 5,6-position of the furo[3,2-g]chromen-7-one system, were prepared by the MacLeod method. 2004 Springer Science + Business Media, Inc.
- Garazd,Garazd,Khilya
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p. 535 - 540
(2007/10/03)
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