1143-70-0Relevant articles and documents
Urolithins, intestinal microbial metabolites of pomegranate ~ellagitannins, exhibit potent antioxidant activity in a cell-based assay
Dobroslawa, Bialonska,Kasimsetty, Sashi G.,Khan, Shabana I.,Daneel, Ferreira
, p. 10181 - 10186 (2009)
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.
Urolithin C, a gut metabolite of ellagic acid, induces apoptosis in PC12 cells through a mitochondria-mediated pathway
Yin, Peipei,Zhang, Jianwei,Yan, Linlin,Yang, Lingguang,Sun, Liwei,Shi, Lingling,Ma, Chao,Liu, Yujun
, p. 17254 - 17263 (2017)
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.
Urolithin as a Converging Scaffold Linking Ellagic acid and Coumarin Analogues: Design of Potent Protein Kinase CK2 Inhibitors
Cozza, Giorgio,Gianoncelli, Alessandra,Bonvini, Paolo,Zorzi, Elisa,Pasquale, Riccardo,Rosolen, Angelo,Pinna, Lorenzo A.,Meggio, Flavio,Zagotto, Giuseppe,Moro, Stefano
, p. 2273 - 2286 (2011)
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.
Gut Microbiota conversion of dietary ellagic acid into bioactive phytoceutical urolithin a inhibits heme peroxidases
Saha, Piu,Yeoh, Beng San,Singh, Rajbir,Chandrasekar, Bhargavi,Vemula, Praveen Kumar,Haribabu, Bodduluri,Vijay-Kumar, Matam,Jala, Venkatakrishna R.
, (2016)
Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to interindividual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical- based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunitymicrobiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiotamediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut.
Urolithin and reduced urolithin derivatives as potent inhibitors of tyrosinase and melanogenesis: Importance of the 4-substituted resorcinol moiety
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
, (2021/05/29)
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.
Synthesis, Characterization, Molecular Docking, and Biological Activities of Some Natural and Synthetic Urolithin Analogs
Noshadi, Bahareh,Ercetin, Tugba,Luise, Chiara,Yuksel, Mine Yarim,Sippl, Wolfgang,Sahin, Mustafa Fethi,Gazi, Mustafa,Gulcan, Hayrettin Ozan
, (2020/07/24)
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.
Synthetic method of urolithin A
-
, (2020/12/08)
The invention discloses a synthetic method of urolithin A. The synthetic method comprises the steps of coupling, primary protective group removal, sulfonylation, carboxylation-lactonization, secondaryprotective group removal and the like. The method provided by the invention is a novel method for synthesizing urolithin A, the raw material is cheap and easy to obtain, the used reaction reagent issmall in environmental pollution and simple in route, and the method can be used for large-scale preparation of urolithin A.
Urolithin A and B Derivatives as ON-OFF Selective Fluorescent Sensors for Iron(III)
Fallah, Amirhossein,Noshadi, Bahareh,Gazi, Mustafa,Gülcan, Hayrettin Ozan
, p. 113 - 120 (2020/01/06)
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.
Urolithins as immune response enhancers
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Page/Page column 30-31, (2020/11/23)
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.
UROLITHINS-CONTAINING AQUEOUS SOLUTION, DRIED SOLID COMPOSITION THEREOF AND PRODUCTION METHOD THEREFOR, AND UROLITHINS STABILIZING METHOD
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Paragraph 0125-0126, (2019/02/19)
A urolithin-containing aqueous solution containing urolithin and collagen, a dried solid composition thereof, methods for producing these, and a stabilization method for urolithin.