- Therapeutic evaluation of synthetic peucedanocoumarin III in an animal model of Parkinson’s disease
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The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.
- Ham, Sangwoo,Kim, Heejeong,Yoon, Jin-Ha,Kim, Hyojung,Song, Bo Reum,Choi, Jeong-Yun,Lee, Yun-Song,Paek, Seung-Mann,Maeng, Han-Joo,Lee, Yunjong
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- A One-Pot Synthesis of Pyranocoumarins Through Microwave-Promoted Propargyl Claisen Rearrangement/Wittig Olefination
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The reaction between propargyl ethers of hydroxybenzaldehydes and the ylide ethyl (triphenylphosphoranylidene)acetate was carried out under microwave irradiation to regioselectively afford angular pyranocoumarins. The chromene and coumarin heterocyclic scaffolds were simultaneously formed in the same synthetic step without changing the reaction conditions. The natural products seselin, braylin, and dipetalolactone were among the products synthesized by this method.
- Schmidt, Bernd,Schultze, Christiane
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p. 223 - 227
(2018/01/26)
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- ISOSAMIDIN ANALOG AND SAMIDIN ANALOG PRODUCTION METHOD
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PROBLEM TO BE SOLVED: To provide a simple method of industrial-scale production of an isosamidin analog or samidin analog. SOLUTION: In the production method, a compound represented by the formula (1) in the figure is 1) senecioylated and 2) acetylated. [X is O or the like; R1 are each independently a C1-3 alkyl group or the like; R2 is H or the like; R3 are each a C1-3 alkyl group; m is an integer from 0 to 2; n is 1 or 2; and the symbol * represents an asymmetric center.] SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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- Antidiabetic effect, antioxidant activity, and toxicity of 3′,4′-Di-O-acetyl-cis-khellactone in Streptozotocin-induced diabetic rats
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Pyranocoumarins are compounds with an important pharmacological profile, such as anti-inflammatory, antioxidant, cytotoxic, antiviral, antibacterial, and hypoglycemic effects. These molecules have a widespread presence as secondary metabolites in medicinal plants used to treat Diabetes Mellitus (DM). The aim of this work was to evaluate antidiabetic activity in Streptozotocin (STZ)-induced diabetic rats and the antioxidant effects of 3′,4′-Di-O-acetyl-cis-khellactone (DOAcK), as well as its toxic potential. We obtained DOAcK with an enantiomeric excess of 70% by chemical synthesis. Our results showed that this compound exerts an important antidiabetic effect: blood glucose decreased in groups treated with DOAcK by 60.9% at dose of 15?mg/kg (p?50) >2000?mg/kg and, at this dose, no signs of toxicity or death were reported after 14?days of observation. These results indicate that DOAcK can improve glucose metabolism, which may be due to the increased antioxidant activity of CAT, GPx and SOD. In addition, DOAcK is not toxic in the studies tested.
- Domínguez-Mendoza, Elix Alberto,Cornejo-Garrido, Jorge,Burgue?o-Tapia, Eleuterio,Ordaz-Pichardo, Cynthia
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supporting information
p. 4086 - 4091
(2016/08/01)
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- Cp?Co(III)-Catalyzed Annulations of 2-Alkenylphenols with CO: Mild Access to Coumarin Derivatives
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Cp?Co(III)-catalyzed annulations of 2-alkenylphenols with CO for the synthesis of coumarin derivatives have been developed. The reaction features mild reaction conditions, broad substrate scope, and good functional group tolerance. Preliminary mechanistic studies were conducted, suggesting that C-H activation is the turnover limiting step. Furthermore, the efficiency of this reaction was demonstrated by the rapid total synthesis of three natural products herniarin, xanthyletin, and seselin.
- Liu, Xu-Ge,Zhang, Shang-Shi,Jiang, Chun-Yong,Wu, Jia-Qiang,Li, Qingjiang,Wang, Honggen
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supporting information
p. 5404 - 5407
(2015/11/18)
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- Towards heterogeneous organocatalysis: Chiral iminium cations supported on porous materials for enantioselective alkene epoxidation
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Enantiomerically pure iminium cations have been supported on a microporous support (zeolite Y) and on a mesoporous support (Al-MCM-41). These materials are effective asymmetric catalysts for the epoxidation of a range of aryl alkenes, giving high conversions quickly and with enantioselectivities similar to or in some cases even higher than are achievable using the corresponding iminium tetraphenylborates under homogeneous conditions. The catalysts can be simply recycled by filtration and washing. The methodology is illustrated in the synthesis of two natural products, (-)-(3′S)-lomatin and (+)-(3′S,4′R)-trans-khellactone, showing the general efficacy of our approach. The Royal Society of Chemistry 2013.
- Bulman Page, Philip C.,Mace, Andrew,Arquier, Damien,Bethell, Donald,Buckley, Benjamin R.,Willock, David J.,Hutchings, Graham J.
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p. 2330 - 2339
(2013/09/02)
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- Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor
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The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC50 value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5- methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC50 values 25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.
- Marumoto, Shinsuke,Miyazawa, Mitsuo
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supporting information; experimental part
p. 784 - 788
(2012/03/22)
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- Gold nanoparticles supported on TiO2 catalyse the cycloisomerisation/oxidative dimerisation of aryl propargyl ethers
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Gold nanoparticles supported on TiO2 (~1%) catalyse in high yields the selective cycloisomerisation of aryl propargyl ethers into the corresponding 2H-chromenes, under heterogeneous conditions. 2H,2′H-3, 3′-Bichromenes resulting from a catalytic oxidative dimerization pathway are also formed as by-products. The Royal Society of Chemistry 2011.
- Efe, Christina,Lykakis, Ioannis N.,Stratakis, Manolis
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supporting information; body text
p. 803 - 805
(2011/04/12)
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- Anti-AIDS agents 83. Efficient microwave-assisted one-pot preparation of angular 2,2-dimethyl-2H-chromone containing compounds
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A novel and efficient microwave-assisted one-pot reaction was developed to synthesize angular 2,2-dimethyl-2H-chromone-containing compounds, which is the first and key step in the synthesis of potent DCK and DCP anti-HIV agents. The newly developed microwave synthesis conditions dramatically shortened the reaction time from 2 days to 4 h with improved yields.
- Zhou, Ting,Shi, Qian,Lee, Kuo Hsing
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experimental part
p. 4382 - 4386
(2010/09/12)
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- Highly enantioselective total synthesis of (-)-(3'S)-lomatin and (+)-(3'S,4'/?)-frans-khellactone
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Concise highly enantioselective three-step syntheses are described for (-)-(3'S)-lomatin and (+)-(3'S,4'fl)-frans-khellactone from 7-hydroxy- coumarin in 97% ee and in 57% and 58% overall yields, respectively, using nonaqueous enantioselective epoxidation
- Page, Philip C. Bulman,Appleby, Louise F.,Day, David,Chan, Yohan,Buckley, Benjamin R.,Allin, Steven M.,McKenzie, Michael J.
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supporting information; experimental part
p. 1991 - 1993
(2009/09/08)
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- Pharmaceutical Composition Useful as Acetylcholinesterase Inhibitors
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A pharmaceutical composition useful as acetylcholinesterase inhibitors. The present invention relates to pharmaceutical composition comprising the naturally occurring compounds selected from (±) Marmesin, Columbianetin, Dihydroxanthyletin and substituted coumarin derivatives of 7-allyloxy coumarin, 7-benzyloxy coumarin, 7-methoxy coumarin, 7-acetyloxy coumarin, 4-methyl-7-hydroxy coumarin and 4-methyl-7-acetyloxy coumarin. The said compositions posses a high degree of acetylcholinesterase inhibitory (AChE) property.
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Page/Page column 3
(2008/06/13)
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- A concise route for the synthesis of biologically interesting pyranocoumarins - Seselin, (±)-cis-khellactone, (±)- quianhucoumarin D, and the (±)-5-deoxyprotobruceol-I regioisomer
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An efficient synthesis of pyranocoumarins is achieved starting from 2H-pyrans. This process provides naturally occurring seselin, cis-khellactone, quianhucoumarin D, and the 5-deoxyprotobruceol-I regioisomer. Georg Thieme Verlag Stuttgart.
- Lee, Yong Rok,Lee, Won Kyong,Noh, Seok Kyun,Lyoo, Won Seok
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p. 853 - 859
(2007/10/03)
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- Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans
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Herein we report a novel strategy for the design and construction of natural and natural product-like libraries based on the principle of privileged structures, a term originally introduced to describe structural motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugural template for the construction of natural product-like libraries via this strategy. Initially, a novel solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that relies on the use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated through the construction of six focused combinatorial libraries designed around natural and designed molecules of recent biological interest.
- Nicolaou,Pfefferkorn,Roecker,Cao,Barluenga,Mitchell
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p. 9939 - 9953
(2007/10/03)
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- Anti-AIDS agents 31. Synthesis and anti-HIV activity of 4-substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) thiolactone analogs
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Four DCK-thiolactone analogs (3-6) were synthesized asymmetrically and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. Based on the functionality on the thiolactone-coumarin nucleus, activity was in the order: methyl > H > propyl > benzyl. 4-Methyl-3',4'-di- O-(-)-camphanoyl-(+)-cis-khelthiolactone (4) exhibited extremely potent anti- HIV activity with EC50 and therapeutic index values of 0.00718 μM and > 21,300, respectively.
- Yang, Zheng-Yu,Xia, Yi,Xia, Peng,Cosentino, L. Mark,Lee, Kuo-Hsiung
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p. 1483 - 1486
(2007/10/03)
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- Microwave Promoted and Improved Thermal Synthesis of Pyranocoumarins and Furocoumarins
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Propargyl ethers of 7-hydroxy-, 4-hydroxy-, and 4-methyl-7-hydroxycoumarins have been efficiently rearranged to pyranocoumarins and furocoumarins under microwave irradiation; improved thermal rearrangement of these ethers was also reported.
- Saidi, Mohammad R.,Bigdeli, Kamal
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p. 800 - 801
(2007/10/03)
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- Cesium fluoride-mediated claisen rearrangements of phenyl propargyl ethers: Substituent effects of an orthoalkoxy group on the benzene ring or modified propargyl residues
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The expected 7-alkoxy-2-methylbenzo[b]furans were effectively given in the CsF-mediated Claisen rearrangement of phenyl propargyl ethers with an o-alkoxy substituent on the benzene ring. On the other hand CsF did not affect the production of the corresponding benzo[b]furans when ethers, carrying a propargyl residue modified by either 1,1-dimethyl or 3-ethoxycarbonyl functions, were used as substrates in the rearrangement.
- Ishikawa, Tsutomu,Mizutani, Akiko,Miwa, Chizue,Oku, Yumie,Komano, Naoko,Takami, Atsuya,Watanabe, Toshiko
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p. 2261 - 2272
(2007/10/03)
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- Convenient Two-step Syntheses of Seselin and Angelicin Derivatives
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Convenient two-step approaches are described for the syntheses of seselin (3a), seselin and angelicin derivatives (3b-d and 5a-d) from 2,4-dihydrobenzaldehyde (1a) and 2,4-dihydroxyacetophenone (1b) using tandem Claisen rearrangement and Wittig reaction.
- Mali, Raghao S.,Pandhare, Nalini A.,Sindkhedkar, Milind D.
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p. 7109 - 7110
(2007/10/02)
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- Natural Product Chemistry. Part 181. Investigations on the Synthesis of Dihydropyrano- and Dihydrofurano-coumarins by Application of Catalytic Enantioselective cis-Dihydroxylation
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As part of a study on the applicability of catalytic enantioselective cis-dihydroxylation for the synthesis of dihydropyrano- and dihydrofurano-anellated coumarins new routes to (-)-cis-khellactone 1b, (-)-trans-khellactone 1c and rutaretin 4 have been developed.
- Reisch, Johannes,Voerste, Arnd A. W.
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p. 3251 - 3256
(2007/10/02)
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- SYNTHESIS OF THE NATURAL COUMARINS, MURRAOL (CM-c2), TRANS-DEHYDROOSTHOL AND SWIETENOCOUMARIN G
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The coumarin CM-c2 from Cnidium monnieri, 7-methoxy-8-(3-hydroxy-3-methylbut-1-enyl)coumarin, has been synthesized by palladium acetate-catalysed condensation of 7-methoxy-8-iodocoumarin with 2-methylbut-3-en-2-ol.Its stereochemistry follows from its conversion to trans-dehydroosthol.The identity of CM-c2 and murraol has been established.Swietenocoumarin G has been prepared similarly from bergaptol. - Keywords: Cnidium monnieri; Umbelliferae; fruit; coumarin syntheses; CM-c2; murraol; trans-dehydroosthol; swietenocoumarin G.Keywords: Cnidium monnieri; Umbelliferae; fruit; coumarin synthese; CM-c2; murraol; trans-dehydroosthol; swietenocoumarin G.
- Murray, Robert D. H.,Zeghdi, Saad
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p. 227 - 230
(2007/10/02)
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- CYCLODEHYDROGENATION OF ORTHO-(3,3-DIMETHYLALLYL)PHENOLS WITH TRITYL TETRAFLUOROBORATE
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Trityl tetrafluoroborate has been shown to effect the cyclodehydrogenation of o-(3,3-dimethylallyl)phenols in an efficient manner.
- Barua, P.,Barua, N. C.,Sharma, R.P.
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p. 5801 - 5804
(2007/10/02)
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- Studies on Rutaceae: Part II - Chemical Investigations of the Constituents of Atlantia Wightii, Limon creniaulata, Feronia limonia, Citrus limon and Synthesis of Luvangetin, Xanthyletin and Marmin
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Four different species of Rutaceae belonging to the genera Atalantia, Limonia, Feronia and Citrus have been subjected to thorough chemical investigation.Convenient and simple syntheses of luvangetin (II), a major constituent of Limonia crenulata, xanthyletin (I), obtained from Citrus limon and marmin (IX), a lactonic constituent of Feronia limonia, have been described.
- Banerji, J.,Ghoshal, N.,Sarkar, S.,Kumar, M.
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p. 496 - 498
(2007/10/02)
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- Lewis Acid Catalysed Reactions of Coumarins: 7-Methoxy-8-(3'-methylbut-2'-enyl)coumarin (Osthol) and 7-Methoxy-8-(1',2'-epoxy-3'-methylbut-3'-enyl)coumarin (Phebalosin) and PMR Identification of Friedel-Crafts Reaction Products of Toluene and Xylene
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The transformation of the coumarins, 7-methoxy-8-(3'-methylbut-2'-enyl)coumarin (Osthol, I) and 7-methoxy-8-(1',2'-epoxy-3'-methylbut-3'-enyl)coumarin (phebalosin, XV) in the presence of various Lewis acids has been studied.Osthol (I) on treatment with anisole in the presence of aluminium chloride affords 7-methoxy-8-(3'-anisyl)isopentyl-(V)- and 7-methoxy-8-(3'-p-hydroxyphenyl)isopentyl-(VI)-coumarins in addition to 7-hydroxy-8-isopentylcoumarin (IV) while with chlorobenzene as solvent the usual disproportionation product (IV) is produced.It is further observed that toluene is converted into 2,7-(VIII)- and 2,6-(IX)-dimethyl anthracenes and xylene (o-,m- and p-) into 2,3,6,7-tetramethylanthracene (X), all these compounds being characterised from their detailed NMR analysis.Phebalosin (XV) in the presence of boron trifluoride etherate furnishes 7-methoxy-8-(1'-formyl-2'-methylprop-1'-enyl)coumarin (XVI) while with boron tribromide 2'-bromoseselin is produced.
- Banerji, J.,Bhaduri, N.,Rej, R. N.,Shoolery, J. N.,Mukherjee, S.,Bhattacharya, S.
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p. 341 - 345
(2007/10/02)
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