- Synthesis and pharmacological characterisation of arctigenin analogues as antagonists of AMPA and kainate receptors
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(-)-Arctigenin and a series of new analogues have been synthesised and then tested for their potential as AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors expressed in HEK293 cells using a Ca2+ influx assay. In general, these compounds showed antagonist activity at both receptors with greater activity evident at AMPARs. Schild analysis indicates that a spirocyclic analogue 6c acts as a non-competitive antagonist. Molecular docking studies in which 6c was docked into the X-ray crystal structure of the GluA2 tetramer suggest that (-)-arctigenin and its analogues bind in the transmembrane domain in a similar manner to the known AMPA receptor non-competitive antagonists GYKI53655 and the antiepileptic drug perampanel. The arctigenin derivatives described herein may serve as novel leads for the development of drugs for the treatment of epilepsy. This journal is
- Butts, Craig P.,Collingridge, Graham L.,Jane, David E.,Mallah, Shahida,Molnár, Elek,Re?nik, Lisa-Maria,Thatcher, Robert J.,Willis, Christine L.
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supporting information
p. 9154 - 9162
(2021/11/16)
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- Discovery of stereospecific cytotoxicity of (8R,8′R)-trans-arctigenin against insect cells and structure-activity relationship on aromatic ring
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One of the arctigenin stereoisomers, (8R,8′R)-trans-form 1, showed stereospecific cytotoxicity against insect cells, Sf9 and NIAS-AeAl-2 cells. By the comparison with other stereoisomers, the most importance of the 8′R stereochemistry for the higher activities was clarified. On the other hand, the wider range of activity level among stereoisomers against cancer cells, HL-60, was not observed. The structure-activity relationship research using derivatives bearing (8R,8′R)-trans-form was performed to show the same level of activities of 3-iodo, 4-iodo, and 3,4-methylenedioxy derivatives 28, 29, and 36 as (8R,8′R)-trans-arctigenin 1. In the examination of thiono derivatives, 4-iodo thiono and 3,4-methylenedioxy thiono derivatives 66, 67 showed similar level of activities to that of (8R,8′R)-trans-arctigenin 1. The expression of ribosomal 28S rRNA gene of Sf9 cells was increased by (8R,8′R)-trans-arctigenin 1, whereas a degradation of DNA was not observed.
- Nishi, Kosuke,Nishimoto, Asuka,Nishiwaki, Hisashi,Sugahara, Takuya,Yamauchi, Satoshi
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supporting information
(2020/04/29)
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- Design and synthesis of novel arctigenin analogues for the amelioration of metabolic disorders
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Analogues of the natural product (-)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (-)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure-activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.
- Duan, Shudong,Huang, Suling,Gong, Jian,Shen, Yu,Zeng, Limin,Feng, Ying,Ren, Wenming,Leng, Ying,Hu, Youhong
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p. 386 - 391
(2015/04/27)
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- Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin
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Objectives This study aimed to characterize the glucuronidation pathway of arctigenin (AR) in human liver microsomes (HLM) and human intestine microsomes (HIM). Methods HLM and HIM incubation systems were employed to catalyse the formation of AR glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards AR was screened. A combination of chemical inhibition assay and kinetic analysis was used to determine the UGT isoforms involved in the glucuronidation of AR in HLM and HIM. Key findings AR could be extensively metabolized to one mono-glucuronide in HLM and HIM. The mono-glucuronide was biosynthesized and characterized as 4′-O-glucuronide. UGT1A1, 1A3, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7 and 2B17 participated in the formation of 4′-O-G, while UGT2B17 demonstrated the highest catalytic activity in this biotransformation. Both kinetic analysis and chemical inhibition assays demonstrated that UGT1A9, UGT2B7 and UGT2B17 played important roles in AR-4′-O-glucuronidation in HLM. Furthermore, HIM demonstrated moderate efficiency for AR-4′-O-glucuronidation, implying that AR may undergo a first-pass metabolism during the absorption process. Conclusion UGT1A9, UGT2B7 and UGT2B17 were the major isoforms responsible for the 4′-O-glucuronidation of AR in HLM, while UGT2B7 and UGT2B17 were the major contributors to this biotransformation in HIM.
- Xin, Hong,Xia, Yang-Liu,Hou, Jie,Wang, Ping,He, Wei,Yang, Ling,Ge, Guang-Bo,Xu, Wei
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p. 1673 - 1681
(2016/01/26)
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- New Butyrolactone Type Lignans from Arctii Fructus and Their Anti-inflammatory Activities
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Arctiidilactone (1), a novel rare butyrolactone lignan with a 6-carboxyl-2-pyrone moiety, and 11 new butyrolactone lignans (2-12) were isolated from the fruits of Arctium lappa L., together with 5 known compounds (13-17). Their structures were elucidated by interpretation of their spectroscopic data (1D and 2D NMR, UV, IR, ORD, and HRESIMS) and comparison to literature data. The absolute configurations of compounds 1-12 were determined by a combination of rotating-frame nuclear Overhauser effect spectroscopy (ROESY), circular dichroism (CD) spectroscopy, and Rh2(OCOCF3)4-induced CD spectroscopy. All of the compounds were tested for their anti-inflammatory properties in terms of suppressing the production of NO in lipopolysaccharide-induced BV2 cells. Compounds 1, 6, 8, and 10 exhibited stronger anti-inflammatory effects than the positive control curcumin, particularly 1, which exhibited 75.51, 70.72, and 61.17% inhibition at 10, 1, and 0.1 μM, respectively.
- Yang, Ya-Nan,Huang, Xiao-Ying,Feng, Zi-Ming,Jiang, Jian-Shuang,Zhang, Pei-Cheng
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p. 7958 - 7966
(2015/09/28)
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- Biopreparation of an anti-inflammatory agent, diarctigenin, from arctiin isolated from Arctium lappa by Rhizoctonia solani AG-4
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In the preliminary screening for the plant-derived pesticides against Rhizoctonia solani Kühn AG-4 (RS AG-4), the indicator compounds arctiin (1) and arctigenin (2) in methanol extracts of Arctium lappa L. were consumed and transformed to other compounds. Thus, in the present study RS AG-4 was used as a biocatalyst and the biotransformation of arctiin (1) was investigated. Conversion of arctiin (1) to arctigenin (2) was achieved by the enzymatic hydrolysis of sugar moiety. In addition, an anti-inflammatory lignan dimer reported from the Arctium species, diarctigenin (3) was afforded in good yields. The HPLC monitoring of the biotransformation process indicated the possible mechanism. It would be an excellent method to produce large scale of diarctigenin (3) for the successive medicinal examinations.
- Kuo, Ping-Chung,Chen, Zi-Yu,Chen, Miao-Fan
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supporting information
p. 6955 - 6958
(2019/04/10)
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- Potent anti-platelet constituents from centaurea iberica
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New naturally occurring nitrogenous compounds 1 and 2, along with a new dimeric lignan glucoside 3, have been isolated from the ethyl acetate soluble fraction of Centaurea iberica. Their structures have been elucidated through spectroscopic techniques. All the isolated compounds showed significant platelet aggregation inhibition.
- Khan, Amna Nisar,Fatima, Itrat,Khaliq, Urooj Abdul,Malik, Abdul,Miana, Ghulam Abbas,Qureshi, Zia-Ur-Rehman,Rasheed, Huma
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experimental part
p. 2053 - 2064
(2011/05/07)
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- Radical carboxyarylation approach to lignans. Total synthesis of (-)-arctigenin, (-)-matairesinol, and related natural products
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Total syntheses of seven biologically important lignan natural products, including (-)-arctigenin, (-)-matairesinol, and (-)α-conidendrin, by way of a highly stereoselective domino radical sequence is presented. The reported stereochemistry of the natural product 7-hydroxyarctigenin is shown to be erroneous; a diastereoisomeric structure is assigned to the natural product.
- Fischer, Joshua,Reynolds, Aaron J.,Sharp, Lisa A.,Sherburn, Michael S.
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p. 1345 - 1348
(2007/10/03)
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- Preparation of tetrahydrodibenzocyclooctene lignans and spirodienones by hypervalent iodine oxidation of phenolic dibenzylbutyrolactones
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Treatment of the dibenzylbutyrolactone 18 with PhI(OCOCF3)2 in trifluoroethanol gives as the major product either the spirodienone 28 or the tetrahydrodibenzocyclooctene 29, depending upon the length of time allowed for the reaction. Reaction of a second dibenzylbutyrolactone 19 under the same conditions gives the products 33, 34, 36 and 38, while 20 gives 43 directly. These reactions provide the first syntheses of spirodienones such as 28 and 33, which have been postulated as intermediates in the biosynthesis of tetrahydrodibenzocyclooctene lignans.
- Ward, Robert S.,Pelter, Andrew,Abd-El-Ghani, Atef
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p. 1303 - 1336
(2007/10/03)
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- Intramolecular regioselective insertion into unactivated prochiral carbon-hydrogen bonds with diazoacetates of primary alcohols catalyzed by chiral dirhodium(II) carboxamidates. Highly enantioselective total synthesis of natural lignan lactones
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Intramolecular insertion into unactivated prochiral C-H bonds of 3-aryl-1-propyl diazoacetates catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)-carboxylate], Rh2(4R-MPPIM)4 or Rh2(4S-MPPIM)4, occurs in 91-96% ee and with virtually complete regiocontrol for the formation of β-benzyl-γ-butyrolactones. This methodology has been applied to the total synthesis of dibenzylbutyrolactone lignans (-)- and (+)-enterolactone, (-)- and (+)-hinokinin, and (+)-arctigenin from substituted cinnamic acids in 19-27% overall yields. Aryltetralin lignan (+)-isodeoxypodophyllotoxin was prepared from the reactant 3,4-(methylenedioxy)cinnamic acid in 36% yield overall, and the lactone precursor to (+)-isolauricerisinol was formed in 96.5% ee and 23% yield overall. Applications of the chiral Rh2(MPPIM)4 catalysts to fully aliphatic systems resulting in the formation of β-substituted-γ-butyrolactones with high regiocontrol and with 93-96% ee have demonstrated the generality of this methodology. A model that provides accurate predictions of β-substituted-γ-butyrolactone absolute configurations in these asymmetric metal carbene transformations is described.
- Bode,Doyle,Protopopova,Zhou
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p. 9146 - 9155
(2007/10/03)
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- FORMATION OF (-)-ARCTIGENIN IN FORSYTHIA INTERMEDIA
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Forsythia intermedia cell-free extracts were examined for their ability to catalyse the enantioselective and regiospecific O-methylation of matairesinol.In contrast to the enzymatic steps defined from (+)-pinoresinol to (-)-matairesinol, the conversion of matairesinol into arctigenin was not highly enenatioselective; both (+)- and (-)-antipodes of matairesinol served as substrates for methylation, with the naturally occuring (-)-enantiomer slightly preferred.But the cell-free extracts also catalyses the synthesis of (+)- and (-)-isoarctigenins, with (-)-matairesinol again the preferred substrate.Thus the O-methylation of matairesinol, catalysed by F. intermedia cell-free extracts, is neither highly enantioselective nor regiospecific.No evidence that subsequent methylation of either arctigenin or isoarctigenin occured to afford dimethyl matairesinol was obtained, i.e. the O-methyltransferase(s) only catalysed monomethylation.Taken together, it is proposed that post-coupling methylation does not proceed via regiospecific methylation of matairesinol to give arctigenin directly.Instead, regiospecific glucosylation first occurs to afford matairesinoside; subsequent methylation affords arctiin, which is then converted into arctigenin via action of a β-glucosidase. Key Word Index - Forsythia; Oleaceae; O-methyltransferases; glucosyltransferases; lignans; neolignans; biosynthesis; enantioselectivity; regiospecifity; chiral separation.
- Ozawa, Shuji,Davin, Laurence B.,Lewis, Norman G.
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p. 643 - 652
(2007/10/02)
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- LIGNANES.10. PREPARATION DES (R)-(+) ET (S)-(-)-β-PIPERONYL ET β-VERATRYL-γ-BUTYROLACTONES ET LEUR UTILISATION DANS LA SYNTHESE TOTALE DE LIGNANES OPTIQUEMENT ACTIFS
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A simple and efficient route leading to optically active β-benzyl-γ-butyrolactones is described.Thus, the methyl (R,S)-α-benzylhemisuccinate resulting from a Stobbe condensation with an appropriate aromatic aldehyde, followed by catalytic hydrogenation of the intermediate α-benzylidene hemisuccinic ester, was resolved by means of a chiral base (ephedrine or α-methyl benzylamine).Reduction of each enantiomer, using calcium borohydride, then led to the corresponding optically active β-benzyl-γ-butyrolactone.In this way, the following two lactones were obtained in both (R)-(+) and (S)-(-) enantiomeric forms, β-piperonyl- and β-veratryl-γ-butyrolactones 1 and 2 respectively.These lactones were used as key-intermediates for the syntheses of 17 optically active lignans and lignoids, such as (-)-dimethylmatairesinol (-)-23, (-)-kusunokinin (-)-26 and (+)-dimethylisolariciresinol (+)-35.
- Brown, Eric,Daugan, Alain
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p. 141 - 154
(2007/10/02)
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- Oxidative Coupling of Lignans. IV. Monophenolic Oxidative Coupling
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Oxidative coupling of the monophenolic monoester (6) gives an aryltetralin (12) which is a potential intermediate for the synthesis of clinically active monophenolic lignan lactones.In contrast, oxidative couplings of the monophenols (32) and (35), derived from matairesinol (29), give mixtures of diastereoisomeric cyclooctadiene lignans while 4'-demethyldeoxypodorhizon (26) does not cyclize.These results show that the degree of aromatic substitution in monophenolic diarylbutanes plays an important role in determining the outcome of oxidative coupling.An alternative synthesis of the lactone (57) from piperonal has been investigated.
- Burden, Jonathan K.,Cambie, Richard C.,Craw, Peter A.,Rutledge, Peter S.,Woodgate, Paul D.
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p. 919 - 933
(2007/10/02)
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- Prestegane A, from Steganotaenia araliacea Hochst.: The First Neutral Dibenzylbutanolide Lignan with a meta-Phenol - A Short Synthesis of cis and trans (+/-) Arctigenin -
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A potential biogenetic precursor of steganes was isolated and its structure 1c was determined using high resolution PMR, total synthesis and comparison with (+/-) arctigenin resulting from an unequivocal synthesis.
- Taafrout, Mohamed,Rouessac, Francis,Robin, Jean-Pierre
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p. 3237 - 3238
(2007/10/02)
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