- 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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- Electrochemical Intramolecular C—H/O—H Cross-Coupling of 2-Arylbenzoic Acids
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A synthetic protocol to lactones by electro-oxidative induced C—H activation of 2-arylbenzoic acids has been developed. By using Na2SO4 aqueous solution as a cheap and green supporting electrolyte, different 2-arylbenzoic acids could provide the corresponding lactones in 30%—90% yields. This reaction could be conducted on a gram scale with a good efficiency as well as a high utility for natural product synthesis.
- Shao, Ailong,Li, Na,Gao, Yong,Zhan, Jirui,Chiang, Chien-Wei,Lei, Aiwen
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- Oxidant-Free C(sp2)-H Functionalization/C-O Bond Formation: A Kolbe Oxidative Cyclization Process
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An anodic oxidation/cyclization of 2-arylbenzoic acids for the synthesis of dibenzopyranones has been developed. The reaction proceeds at room temperature with no oxidant or electrolyte required and exhibits a high atom economy with H2 being th
- Zhang, Lei,Zhang, Zhenxing,Hong, Junting,Yu, Jian,Zhang, Jianning,Mo, Fanyang
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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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- Copper catalyzed room temperature lactonization of aromatic C-H bond: A novel and efficient approach for the synthesis of dibenzopyranones
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We have developed a novel and efficient methodology for the intramolecular aryl C-H oxidative lactonization of 2-arylbenzaldehyde using a low-cost CuCl catalyst and TBHP as the oxidant at room temperature. We applied the methodology to the synthesis of a series of dibenzopyranones.
- Singha, Raju,Dhara, Shubhendu,Ghosh, Munmun,Ray, Jayanta K.
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- Mild ArI-catalyzed C(sp2)-H or C(sp3)-H functionalization/C-O formation: An intriguing catalyst-controlled selectivity switch
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A tandem C(sp2)H and C(sp3)H functionalization/CO bond formation catalyzed by iodine(III) reagents generated in situ has been developed. The method shows wide scope under mild conditions and exhibits an unprecedented selectivity profile that can be switched depending on the catalyst employed.
- Wang, Xueqiang,Gallardo-Donaire, Joan,Martin, Ruben
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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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- Vitamin Catalysis: Direct, Photocatalytic Synthesis of Benzocoumarins via (-)-Riboflavin-Mediated Electron Transfer
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An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (-)-riboflavin (vitamin B2) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis.
- Morack, Tobias,Metternich, Jan B.,Gilmour, Ryan
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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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- 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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- Visible-Light-Induced Arene C(sp 2)-H Lactonization Promoted by DDQ and tert -Butyl Nitrite
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A visible-light photocatalytic aerobic oxidative lactonization of arene C(sp 2)-H bonds proceeds in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tert -butyl nitrite (TBN). Under the optimized conditions, a range of 2-arylbenzoic acids is converted into the corresponding benzocoumarin derivatives in moderate to excellent yields. This method is characterized by its atom economy, mild reaction conditions, the use of a green oxidant and metal-free catalysis.
- Chen, Bajin,Hu, Baoxiang,Hu, Xinquan,Jin, Liqun,Li, Meichao,Shen, Zhenlu,Sun, Nan,Wang, Shengpeng,Wang, Yiqing
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p. 261 - 266
(2020/02/18)
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- Cerium photocatalyzed dehydrogenative lactonization of 2-arylbenzoic acids
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The first cerium photocatalyzed dehydrogenative lactonization of 2-arylbenzoic acids has been developed. This operationally simple protocol allows rapid access to synthetically useful coumarins on gram scale by employing CeCl3 as a photocatalyst and O2 as a terminal oxidant. Overall, this delivers an economical and environmentally amiable entry to diversely substituted coumarins, important structural motifs in bioactive molecules.
- Wadekar, Ketan,Aswale, Suraj,Yatham, Veera Reddy
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supporting information
p. 983 - 987
(2020/02/15)
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- Photocatalytic oxidation synthesis method of benzocoumarin compound
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The synthesis method disclosed by the invention takes,aryl-aryl formic acid compound as a reaction raw material 2 - to react the substrate in an organic solvent, DEG C - 5555,6-dinitrile - 1111, 4-benzoquinone 2,3 - and tert-butyl nitrite (DDQ) as a catal
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Paragraph 0049; 0050
(2020/03/17)
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- Scalable Electrochemical Dehydrogenative Lactonization of C(sp2/sp3)-H Bonds
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A practical, electrochemical method is developed for the direct dehydrogenative lactonization of C(sp2/sp3)-H bonds under external oxidant- and metal-free conditions, delivering diverse lactones, including coumarin derivatives with excellent regioselectivity. The scalable nature of this newly developed electrochemical process was demonstrated on a 40 g scale following an operationally simple protocol. The remote lactonization of C(sp3)-H bonds would constitute an important synthetic advance toward electrochemical C-O bond formation.
- Zhang, Sheng,Li, Lijun,Wang, Huiqiao,Li, Qian,Liu, Wenmin,Xu, Kun,Zeng, Chengchu
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supporting information
p. 252 - 255
(2018/01/17)
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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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- Ligand- and Base-Free Access to Diverse Biaryls by the Reductive Coupling of Diaryliodonium Salts
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A ligand- and base-free, Pd-catalyzed protocol to access a wide range of symmetrical and unsymmetrical biaryls from stable diaryliodonium salts was developed. The reaction involved the use of an effective and recyclable Pd/polyethylene glycol-400 catalyst system to harness the aryl moieties of two diaryliodonium salts; the ensuing biaryls may be utilized to synthesize an array of useful compounds, including 5-aryluracils, carbazoles, chromenones, fluorenones, phenathridines, and boscalid analogues.
- Arun,Reddy, P. O. Venkataramana,Pilania, Meenakshi,Kumar, Dalip
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p. 2096 - 2100
(2016/05/09)
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- Silver-Catalyzed C(sp2)-H Functionalization/C-O Cyclization Reaction at Room Temperature
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Silver-catalyzed C(sp2)-H functionalization/C-O cyclization has been developed. The scalable reaction proceeds at room temperature in an open flask. The present method exhibits good functional-group compatibility because of the mild reaction conditions. Using a AgNO3 catalyst and a (NH4)2S2O8 oxidant in CH2Cl2/H2O solvent, various lactones are obtained in good to excellent yields. A kinetic isotope effect (KIE) study indicates that the reaction may occur via a radical process.
- Dai, Jian-Jun,Xu, Wen-Tao,Wu, Ya-Dong,Zhang, Wen-Man,Gong, Ying,He, Xia-Ping,Zhang, Xin-Qing,Xu, Hua-Jian
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p. 911 - 919
(2015/01/30)
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- Photocatalytic Dehydrogenative Lactonization of 2-Arylbenzoic Acids
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A metal-free dehydrogenative lactonization of 2-arylbenzoic acids at room temperature was developed. This work illustrates the first application of visible-light photoredox catalysis in the preparation of benzo-3,4-coumarins, an important structural motif in bioactive molecules. The combination of photocatalyst [Acr+-Mes] with (NH4)2S2O8 as a terminal oxidant provides an economical and environmentally benign entry to different substituted benzocoumarins. Preliminary mechanistic studies suggest that this reaction most likely occurs through a homolytic aromatic substitution pathway.
- Ramirez, Nieves P.,Bosque, Irene,Gonzalez-Gomez, Jose C.
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p. 4550 - 4553
(2015/09/28)
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- Regioselectivity of the intramolecular biaryl coupling reaction of 3-substituted phenyl 2-iodobenzoate using a palladium reagent
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This study investigated the regioselectivity of the intramolecular biaryl coupling reaction of the phenyl benzoate derivative which possesses a methyl or methoxy group at the meta-position of the phenoxy moiety. The type of base and the presence/absence of the phosphine ligand influenced the product ratio. A transition state model and the regioselectivity of the reaction are discussed.
- Maeda, Kazuhiro,Matsukihira, Takuya,Saga, Shumpei,Takeuchi, Yasuo,Harayama, Takashi,Horino, Yoshikazu,Abe, Hitoshi
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p. 621 - 628
(2016/11/07)
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- NIS-mediated oxidative lactonization of 2-arylbenzoic acids for the synthesis of dibenzopyranones under metal-free conditions
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A series of dibenzopyranones were synthesized from 2-arylbenzoic acids by a radical oxidative cyclization procedure mediated by N-iodosuccinimide (NIS). The methodology is distinguished by its practicality in terms of its wide substrate scope, good functi
- Gao, Peng,Wei, Yunyang
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supporting information
p. 343 - 347
(2014/02/14)
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- General and practical carboxyl-group-directed remote C-H oxygenation reactions of arenes
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Two methods for remote aromatic C-H oxygenation reactions, have been developed. Method1, the Cu-catalyzed oxygenation reaction, is highly efficient for cyclization of electron-neutral and electron-rich biaryl carboxylic acids into 3,4-benzocoumarins. Method2, the K2S2O 8-mediated oxygenation reaction, is more general and practical for cyclization of substrates with electron-donating and -withdrawing groups (see scheme). Copyright
- Wang, Yang,Gulevich, Anton V.,Gevorgyan, Vladimir
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p. 15836 - 15840
(2014/04/03)
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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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- Pd-catalyzed C-H lactonization for expedient synthesis of biaryl lactones and total synthesis of cannabinol
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A practical Pd(II)/Pd(IV)-catalyzed carboxyl-directed C-H activation/C-O cyclization to construct biaryl lactones has been developed. The synthetic utility of this new reaction was demonstrated in an atom-economical and operationally convenient total synthesis of the natural product cannabinol from commercially available starting materials, with the newly developed method used for two key steps.
- Li, Yan,Ding, Yan-Jun,Wang, Jian-Yong,Su, Yi-Ming,Wang, Xi-Sheng
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supporting information
p. 2574 - 2577
(2013/07/11)
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- Catalyst-free synthesis of diversely substituted 6H-benzo[c]chromenes and 6H-benzo[c]chromen-6-ones in aqueous media under MWI
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In this paper, a catalyst-free synthesis of diversely substituted 6H-benzo[c]chromenes and 6H-benzo[c]chromen-8-ols via cascade reactions of 2-(2-(allyloxy)phenyl)furan and 2-(2-(prop-2-ynyloxy)phenyl)furan, featured with intramolecular Diels-Alder reactions of furan with unactivated alkene/alkyne in aqueous media under MWI, was developed. In addition, an environmentally friendly oxidation of 6H-benzo[c]chromenes into the corresponding benzo[c]chromen-6-ones using aqueous H2O2 as an oxidant, in the absence of any activator/catalyst, was also revealed.
- He, Yan,Zhang, Xinying,Cui, Liangyan,Wang, Jianji,Fan, Xuesen
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p. 3429 - 3435
(2013/01/16)
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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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- Use of 4-cyanocoumarins as dienophiles in a facile synthesis of highly substituted dibenzopyranones
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(Chemical Equation Presented) A new synthesis of dibenzopyranones 14 is reported via the Diels-Alder cycloaddition of 4-cyanocoumarins 12 with 1-silyloxydienes 10 to give the adducts 13 which are then converted into 14 in one step via treatment with base and loss of the cyano and silyloxy groups.
- Jung, Michael E.,Allen, Damian A.
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supporting information; scheme or table
p. 757 - 760
(2009/08/07)
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- Bu3SnH mediated oxidative radical cyclisations: Synthesis of 6H-benzo[c]chromen-6-ones
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Attempts to synthesise 6H-benzo[c]chromen-6-ones by Bu3SnH mediated cyclisation of o-(benzoyl)aryl radicals failed because of the preferred trans conformation of the ester. This problem was overcome by using cyclisation of o-(benzyloxy)aryl and o-[(aryloxy)methyl]aryl radicals to yield 6H-benzo[c]chromenes followed by oxidation to the 6H-benzo[c]chromen-6-ones. 3-Methoxy-6H-benzo[c]chromen-6-one 1, one of the main biologically active constituents of shilajit, a herbal medicine used in countries surrounding the Himalayan mountains, was synthesised using Bu3SnH mediated cyclisation of 1-benzyloxy-2,4-dibromo-5-methoxybenzene 31 to yield 3-methoxy-6H-benzo[c]chromene 25 followed by PCC oxidation of the 6-position. In order to avoid the problems of rearrangement, the aryl radical cyclisation must be designed such that whichever way the spirodienyl intermediate rearranges, the same product is obtained. For instance, the Bu3SnH mediated cyclisation of 1-iodo- and 1-bromo-2-(3-methoxy-phenyloxymethyl)benzenes 22 and 23 respectively gave both the isomers, 1-methoxy-6H-benzo[c]chromenes 24 and 3-methoxy-6H-benzo[c]chromenes 25 via rearrangement of the intermediate spirodienyl radical. The synthesised 6H-benzo[c]chromenes were oxidised in high yield to the corresponding 6H-benzo[c]chromen-6-ones. The mechanism of the 'oxidative' Bu3SnH mediated cyclisation is discussed.
- Bowman, Russell,Mann, Emma,Parr, Jonathan
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p. 2991 - 2999
(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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- Intramolecular Cyclisations of Biphenyl-2-carboxyl Radicals: Evidence for a Π-State Aroyloxyl Radical
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Biphenyl-2-carboxyl radicals generated by homolysis of acyl hypoiodites cyclise intramoleculary giving mainly δ-lactones through Ar2-6 cyclisation. 2'-Alkoxybiphenyl-2-carboxyl radicals do not give the expected Ar1-5 cyclisation product but undergo a homolytic ipso-substitution of the 2'-substituent.The phenanthrene-4-carboxyl radical gives 5H-phenanthropyran-5-one.Consideration of the molecular orbitals involved suggests that the biphenyl-2-carboxyl radicals are in the ?-ground state and have a higher energy, and, therefore, a less thermally accessible Σ-state than the corresponding amido-radicals.It is suggested that acyloxyl radicals which readily decarboxylate have either a Σ-ground state or a thermally accessible excited Σ-state.
- Glover, Stephen A.,Golding, Stephen L.,Goosen, Andre,McCleland, Cedric W.
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p. 842 - 848
(2007/10/02)
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