- 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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- 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 0066-0075
(2021/09/04)
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- Design, synthesis, and biological evaluation of new urolithin amides as multitarget agents against Alzheimer's disease
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A series of urolithin amide (i.e., URO-4–URO-10 and THU-4–THU-10) derivatives was designed and synthesized, and their chemical structures were confirmed with spectroscopic techniques and elemental analysis. The title compounds and synthesis intermediates
- Shukur, Karar T.,Ercetin, Tugba,Luise, Chiara,Sippl, Wolfgang,Sirkecioglu, Okan,Ulgen, Mert,Coskun, Goknil P.,Yarim, Mine,Gazi, Mustafa,Gulcan, Hayrettin O.
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- 3-Hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-6H-benzo[c] chromen-6-one act as on-off selective fluorescent sensors for Iron (III) under in vitro and ex vivo conditions
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Regarding the abundant use of metals for different purposes, it becomes more critical from various scientific and technological perspectives to discover novel agents as selective probes for the detection of specific metals. In our previous studies, we have shown that aqueous solutions of natural urolithins (i.e., hydroxyl-substituted benzo[c]chromen-6-one derivatives) are selective Iron (III) sensors in fluorescence assays. In this study, we have extrapolated these findings to another coumarine compound (i.e., 3-Hydroxy-7,8,9,10- tetrahydro-6H-benzo[c]chromen-6-one) and compared the selective metal binding properties with Urolithin B (i.e., 3-Hydroxy-6H-benzo[c]chromen-6-one). Following the synthesis and structure identification studies, the fluorometric studies pointed out that the lactam group in the structure still persists to be the important scaffold for maintaining selective on-off sensor capacity that renders the compound a selective Iron (III) binding probe. Moreover, for the first time, fluorescence cellular imaging studies concomitant to cytotoxicity assays with the title compounds were also performed and the results displayed the cell-penetrative, safe, and fluorescent detectable characteristics of the compounds in neuroblastoma and glioblastoma cells through servings as intracellular Iron (III) on-off sensors.
- FALLAH, Amirhossein,GüLCAN, Hayrettin Ozan,GAZI, Mustafa,KALKAN, Rasime,SHUKUR, Karar,TERALI, Kerem
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p. 858 - 867
(2021/07/26)
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- Facile preparation of 3,4-benzocoumarins from 2-arylbenzoic acids with NCS and NAI
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– Treatment of 2-arylbenzoic acids with N-chlorosuccinimide (NCS) and NaI at 70 °C under fluorescent lighting condition gave the corresponding 3,4-benzocoumarins in good yields under transition-metal-free condition. It was found that the reactivity of NCS
- Nakamura, Momoko,Togo, Hideo
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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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-
- Is Fe-catalyzed ortho C-H Arylation of Benzamides Sensitive to Steric Hindrance and Directing Group?
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The previously reported Fe-catalyzed ortho C-H arylation of benzamides relied on bi- or tridentate amide groups and specific iron ligands and was sensitive to steric hindrance. By using new mixed titanates, our present protocol accommodates various weakly coordinating benzamides and tolerates high steric hindrance and sensitive functional groups only under the catalysis of FeCl3 and TMEDA. A wide range of privileged condensed ring compounds can thus be facilely accessed.
- Wei, Yi-Ming,Wang, Meng-Fei,Duan, Xin-Fang
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supporting information
p. 6471 - 6475
(2019/08/26)
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- 1,2,3,4-Tetrahydroisoquinoline/2H-chromen-2-one conjugates as nanomolar P-glycoprotein inhibitors: Molecular determinants for affinity and selectivity over multidrug resistance associated protein 1
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A series of coniugates bearing a 1,2,3,4-tetrahydroisoquinoline motif linked to substituted 7-hydroxy-2H-chromen-2-ones was synthesized and assayed through calcein-AM test in Madin-Darby Canine Kidney (MDCK) cells overexpressing P-glycoprotein (P-gp) and closely related multidrug resistance associated protein 1 (MRP1) to probe the interference with efflux mechanisms mediated by P-gp and MRP1, respectively. A number of substituents at C3 and C4 of coumarin nucleus along with differently sized and shaped spacers was enrolled to investigate the effects of focused structural modifications over affinity and selectivity. Linker length and flexibility played a key role in enhancing P-gp affinity as proved by the most potent P-gp modulator (3h, IC50 = 70 nM). A phenyl ring within the spacer (3k, 3l, 3o) and bulkier groups (Br in 3r, Ph in 3u) at coumarin C3 led to derivatives showing nanomolar activity (160 nM 50 350). Molecular docking calculations carried out on a human MDR1 homology model structure contributed to gain insights into the ligands’ binding modes. Some compounds (3d, 3h, 3l, 3r, 3t, 3u) reversed MDR thereby restoring doxorubicin cytotoxicity when co-administered with the drug into MDCK-MDR1 cells.
- Rullo, Mariagrazia,Niso, Mauro,Pisani, Leonardo,Carrieri, Antonio,Colabufo, Nicola Antonio,Cellamare, Saverio,Altomare, Cosimo Damiano
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p. 433 - 444
(2018/10/31)
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- Urolithin B as a Simple, Selective, Fluorescent Probe for Sensing Iron(III) in Semi-Aqueous Solution
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The development of simple, environmental friendly, and cheap reagents with metal binding properties are quite important not only for the treatment of environmental pollution but also for their application in medicine. Within this study, for the first time, we displayed a natural chromen analogue, Urolithin B, as a simple, selective, fluorescent iron (III) sensing probe. Following the synthesis and structure identification studies, the selective metal binding property of the compound was displayed employing fluorescence techniques. Accordingly, urolithin B has the capacity to coordinate selectively to iron (III) with a 3:2 stoichiometry.
- Fallah, Amirhossein,Gülcan, Hayrettin Ozan,Gazi, Mustafa
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p. 1255 - 1259
(2018/09/06)
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- Design, synthesis and characterization of novel urolithin derivatives as cholinesterase inhibitor agents
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Background: Considering the limitations of current cholinesterase inhibitor drugs for the treatment of Alzheimer’s disease, there is ongoing research activities to find out alternative drug candidates. The aryl-spacer-N-benzyl pharmacophore model has been effectively utilized to design various types of cholinesterase inhibitor molecules, including donepezil. Within this research study, we have questioned the significance of the benzyl group within this pharmacophore employing the urolithin derivatives. Urolithins are benzo[c]chromene analogue metabolites of ellagitannins, abundantly found in pomegranate and berry fruits. Methods: Employing the previous experience that urolithin-spacer-N-benzyl yielded out potent cholinesterase inhibitors, we have designed novel benzo[c]chromene derivatives either lacking the benzyl group or possessing benzyl group in isoquinoline moiety lacking free N-C bond rotation. Following the synthesis and structure identification studies the compounds were screened for their potential to inhibit cholinesterase enzymes. Furthermore, the title compounds were also evaluated for their potential to prevent cholinesterase-accelerated amyloid beta aggregation. In the final, the most active compound was examined to find out its interactions with the cholinesterase enzyme employing a molecular docking study. Results: The title compounds displayed varying cholinesterase inhibitory potential. Some of the compounds were found more / comparable activity to the activity of the current drugs employed in clinic. The potential of the title molecules to inhibit amyloid beta aggregation was found poor. Conclusion: The title compounds displayed varying cholinesterase inhibitory potential, implying that the benzyl group is not a must in each design. This was also shown with the molecular docking studies. On the other hand, the beta amyloid aggregation studies have pointed out that cholinesterase inhibition does not guarantee the prevention of cholinesterase-accelerated amyloid beta aggregation.
- Norouzbahari, Maryam,Burgaz, Emine V.,Ercetin, Tugba,Fallah, Amirhossein,Foroumadi, Alireza,Firoozpour, Loghman,Sahin, Mustafa F.,Gazi, Mustafa,Gulcan, Hayrettin O.
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p. 1131 - 1140
(2018/11/01)
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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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- RadH: A Versatile Halogenase for Integration into Synthetic Pathways
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Flavin-dependent halogenases are useful enzymes for providing halogenated molecules with improved biological activity, or intermediates for synthetic derivatization. We demonstrate how the fungal halogenase RadH can be used to regioselectively halogenate a range of bioactive aromatic scaffolds. Site-directed mutagenesis of RadH was used to identify catalytic residues and provide insight into the mechanism of fungal halogenases. A high-throughput fluorescence screen was also developed, which enabled a RadH mutant to be evolved with improved properties. Finally we demonstrate how biosynthetic genes from fungi, bacteria, and plants can be combined to encode a new pathway to generate a novel chlorinated coumarin “non-natural” product in E. coli.
- Menon, Binuraj R. K.,Brandenburger, Eileen,Sharif, Humera H.,Klemstein, Ulrike,Shepherd, Sarah A.,Greaney, Michael F.,Micklefield, Jason
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supporting information
p. 11841 - 11845
(2017/09/20)
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- Palladium-Catalyzed, N-(2-Aminophenyl)acetamide-Assisted Ortho-Arylation of Substituted Benzamides: Application to the Synthesis of Urolithins B, M6, and M7
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Pd-catalyzed, selective, monoarylation of ortho-C-H bonds of various benzamides with aryl/heteroaryl iodides has been realized using N-(2-aminophenyl)acetamide (APA) as a new bidentate directing group for the first time. The reaction was tolerant of a wid
- Reddy, M. Damoder,Blanton, Alexandra N.,Watkins, E. Blake
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p. 5080 - 5095
(2017/05/24)
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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 37
(2015/07/15)
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- COMPOSITIONS COMPRISING UROLITHINS AND USES THEREOF FOR THE STIMULATION OF INSULIN SECRETION
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The present invention relates to a composition comprising urolithin A, urolithin B, urolithin C, urolithin D, or a combination thereof, for the stimulation of insulin secretion, and to the use of a compound chosen among urolithin A, urolithin B, urolithin C, urolithin D, or a combination thereof, intended for the stimulation of insulin secretion. The present invention also relates to a composition comprising an effective amount of urolithin B, urolithin C, urolithin D, or a combination thereof, for the treatment or the prevention of diabetes mellitus, and in particular for the treatment or the prevention of type 2 diabetes, and to the use of a compound chosen among urolithin B, urolithin C, urolithin D, and a combination thereof, intended for the treatment or the prevention of diabetes mellitus, and in particular of type 2 diabetes.
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Page/Page column 20
(2015/05/05)
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- Compositions comprising urolithins and uses thereof for the stimulation of insulin secretion
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The present invention relates to a composition comprising an effective amount of urolithin A, urolithin B, urolithin C, urolithin D, or a combination thereof, for the stimulation of insulin secretion, and to the use of a compound chosen among urolithin A, urolithin B, urolithin C, urolithin D, or a combination thereof, for the stimulation of insulin secretion. The present invention also relates to a composition comprising an effective amount of urolithin B, urolithin C, urolithin D, or a combination thereof, for the treatment or the prevention of diabetes mellitus, and to the use of a compound chosen among urolithin B, urolithin C, urolithin D, and a combination thereof, for the treatment or the prevention of diabetes mellitus.
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Paragraph 0069
(2015/05/05)
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- Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics
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In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2, 3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors, together with a low affinity for H1 receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine.
- Chen, Yin,Lan, Yu,Wang, Songlin,Zhang, Heng,Xu, Xiangqing,Liu, Xin,Yu, Minquan,Liu, Bi-Feng,Zhang, Guisen
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p. 427 - 439
(2014/02/14)
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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 224-225
(2014/01/17)
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- 3-SUBSTITUTED-6H-BENZO[C]CHROMEN-6-ONES AND 3-SUBSTITUTED-7,8,9,10-TETRAHYDRO-6H-BENZO[C]CHROMEN-6-ONES AGAINST SENILE DEMENTIA
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This invention is related with the conversion of xenobiotics to potent ACHE and BCHE inhibitors that have activity comparable to the current ACHE and BCHE inhibitor drugs (i.e., donepezil, rivastigmine, and galantamine).
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Page/Page column 13
(2014/09/03)
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- Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors
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Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer's Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies.
- Gulcan, Hayrettin Ozan,Unlu, Serdar,Esiringu, Ilker,Ercetin, Tugba,Sahin, Yasemin,Oz, Demet,Sahin, Mustafa Fethi
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p. 5141 - 5154
(2015/02/19)
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- Color-tunable fluorescent dyes based on benzo[c]coumarin
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Hurtley condensation was shown to be a perfect tool with which to assemble a diversified library of derivatives of benzo[c]coumarin. Not only do simple resorcinols and ortho-bromobenzoic acids undergo this reaction, but also dihydroxynaphthalenes and 3-bromothiophene-2-carboxylic acid, affording the desired compounds in moderate yields. In the case of naphthalenediols, intriguing regioselectivity is observed, which holds promise for its utilization in the synthesis of previously inaccessible molecules. Further transformation made it possible to obtain benzo[c]coumarin bearing amino and nitro groups at various positions, which served as entry points to prepare complex hybrids of 1,4-benzoxazin-2-ones and benzo[c]coumarins. The hydroxyl group proved to be the synthetic handle, enabling the synthesis of strongly solvatochromic, soluble analogues. The effect of structural variation on photophysical properties was studied in detail for almost 30 compounds. The relationship between the structure and photophysical properties was thoroughly elucidated by comparison with simple analogues (coumarins, benzoxazinones). All of the obtained compounds exhibit moderate to large Stokes shifts (3300-12500 cm-1). The type of π-expansion of the chromophore strongly influences the overall optical phenomena. Compounds possessing alkyl substituents on the benzo[c]coumarin core have much higher fluorescence quantum yields than their analogues bearing amino, fluorine, and other complex substituents. Interestingly, the product possessing a fused coumarin-thiophene skeleton exhibits over twofold higher fluorescence quantum yield than any of its coumarin-benzene analogues. By using either substituted 2-bromobenzoic acids and electron-rich phenols or postfunctionalization of the products of Hurtley condensation, it is possible to access a range of multisubstituted benzo[c]coumarins. Tunable fluorescence quantum yield and solvatochromism, combined with large Stokes shifts, make them good platforms for emission-oriented applications. Copyright
- Krzeszewski, Maciej,Vakuliuk, Olena,Gryko, Daniel T.
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p. 5631 - 5644
(2013/09/12)
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- Cu(I)-mediated lactone formation in subcritical water: A benign synthesis of benzopyranones and urolithins A-C
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Benzopyranones were successfully synthesized using Cu(I)-mediated C-O bond formation in subcritical water. A number of benzopyranone derivatives including polymethoxy benzopyranones, benzopyranopyridones, chromenoindolones, and furochromenones were synthesized in satisfactory yield. This methodology was further applied to synthesize the intestinal microbial metabolites, urolithins A, B, and C, which were found to exhibit potent antioxidant activity.
- Nealmongkol, Prattya,Tangdenpaisal, Kassrin,Sitthimonchai, Somkid,Ruchirawat, Somsak,Thasana, Nopporn
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p. 9277 - 9283
(2013/10/01)
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- 3-HYDROXY-6H-BENZO [C] CHROMENE-6-ONE DERIVATIVE AND MANUFACTURING METHOD THEREOF
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A method of manufacturing a compound or a salt thereof expressed with a formula (III) below, characterized by causing a compound or a salt thereof expressed with a formula (I) below and a compound or a salt thereof expressed with a formula (II) below to r
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Paragraph 0157; 0161
(2013/12/03)
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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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experimental part
p. 2273 - 2286
(2012/04/11)
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- Design, synthesis, and biological evaluation of coumarin derivatives tethered to an edrophonium-like fragment as highly potent and selective dual binding site acetylcholinesterase inhibitors
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A large series of substituted coumarins linked through an appropriate spacer to 3-hydroxy-N,N-dimethylanilino or 3-hydroxy-N,N,N-trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3-hydroxy-N,N-dimethylanilino series was observed with a 6,7-dimethoxy-3-substituted coumarin derivative, which, along with an outstanding affinity (IC50=0.236 nm) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3-hydroxy-N,N,N- trialkylbenzaminium salts display an AChE affinity in the sub-nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure-affinity and structure-selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of π-π stacking interactions in the AChE peripheral binding site.
- Pisani, Leonardo,Catto, Marco,Giangreco, Ilenia,Leonetti, Francesco,Nicolotti, Orazio,Stefanachi, Angela,Cellamare, Saverio,Carotti, Angelo
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p. 1616 - 1630
(2011/11/29)
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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
(2008/06/13)
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- Synthesis and biological activities of some new dibenzopyranones and dibenzopyrans: Search for potential oestrogen receptor agonists and antagonists
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Continuing our search for newer oestrogen agonists or antagonists and extending our work on the exploration of benzopyran related compounds, some new tricyclic molecules bridged between the active molecules of 3,4-diaryl chroman and 2,3-diaryl benzopyrans have been synthesised. Structural modifications at different positions with elements known to impart agonist or antagonist activities have been carried out to prepare the desired molecules. The target compounds were screened for their anti-osteoporotic (agonist) and anti-uterotrophic (antagonist) activities and were found to be moderately active.
- Pandey, Jaya,Jha, Ashok K.,Hajela
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p. 2239 - 2249
(2007/10/03)
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- Modified coumarins. 6. Synthesis of substituted 5,6-benzopsoralens
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Substituted 5H-benzo[c]furo[3,2-g]chromen-5-ones, modified analogs of psoralen that contain a benzene ring annelated at the 5,6-position of a furo[3,2-g]chromen-7-one system, were synthesized from 3-hydroxy-6H-benzo[c] chromen-6-ones.
- Garazd,Ogorodniichuk,Garazd,Khilya
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p. 424 - 433
(2007/10/03)
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- New fluorogenic substrate for the first continuous steroid sulfatase assay
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The screening for new inhibitors of steroid sulfatase requires an efficient test system. To overcome the shortcomings of the available discontinuous fluorimetric assay, several coumarin-type compounds were investigated as potential new substrates. 3,4-Benzocoumarin 7-O-sulfate was found to have appropriate substrate properties for the establishment of the first direct continuous assay of steroid sulfatase. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Bilban, Melitta,Billich, Andreas,Auer, Manfred,Nussbaumer, Peter
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p. 967 - 969
(2007/10/03)
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- Synthesis of 6H-Dibenzopyran-6-ones via Dienone-Phenol Rearrangements of Spiro-3'-ones
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A series of spiro-3'-ones were prepared from metallated benzamides and 4,4-dimethoxycyclohexadienone.Rearrangement of these spirodienones under a variety of conditions gave substituted 6H-dibenzopyran-6-ones.Rearrangements in aqueous sulfuric acid gave products of formal O-migration while rearrangements in trifluoroacetic anhydride-trifluoroacetic acid-sulfuric acid usually gave C-migration products.Key Words: dienone-phenol rearrangement; 6H-dibenzopyran-6-one, spiro-3'-one
- Hart, David J.,Kim, Adrienne,Krishnamurthy, Ramanarayanan,Merriman, Gregory H.,Waltos, Anne-Marie
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p. 8179 - 8188
(2007/10/02)
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