- Evaluation of coumarin and neoflavone derivatives as HCV NS5B polymerase inhibitors
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Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket-1 (TP-1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A- and B-rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC50 values between 17 and 63 μm. Of these, the newly synthesized 6,8-diallyl-5,7-dihydroxycoumarin (8a) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB-34. The binding site of 8a was mapped to TP-1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP-1 site binders. NS5B-TP-1-8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.
- Nichols, Daniel B.,Leao, Raquel A. C.,Basu, Amartya,Chudayeu, Maksim,de Moraes, Paula De F.,Talele, Tanaji T.,Costa, Paulo R. R.,Kaushik-Basu, Neerja
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- 1H AND 13C NMR SPECTRA AND THE STRUCTURE OF A NEW COUMARIN, C-GLYCOSIDE DAUROSIDE D, FROM Haplophyllum dauricum
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On the basis of chemical transformation, 1H and 13C NMR spectra, tha structure of dauroside D isolated from Haplophyllum dauricum has been established as 6-C-β-D-glucopyranosyl-5,7-dihydroxycoumarin.Some interesting features of the 1H NMR spectra of its acetate have reported and an assignment of the signals in its 1H and 13C NMR spectra has been made.Dauroside D is the first natural coumarin C-glycoside.
- Vdovin, A. D.,Batsuren, D.,Batirov, E. Kh.,Yagudaev, M. R.,Malikov, V. M.
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- Use of microwave irradiation and solid acid catalysts in an enhanced and environmentally friendly synthesis of coumarin derivatives
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Condensation of phenol, 1,3-dihydroxybenzene and 1,3,5- trihydroxybenzene with propynoic and propenoic acids and ethyl acetoacetate using solid acid catalysts and microwave irradiation produces coumarins in excellent yields. The use of heterogeneous catalysts eliminates the production of acidic waste streams associated with conventional (Lewis) acid catalysts. This quick, efficient and environmentally friendly procedure permits the synthesis of substituted coumarins as well as coumarins without 4-alkyl substituents, which are the most difficult to synthesize.
- De La Hoz, Antonio,Moreno, Andrés,Vázquez, Ester
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- Biomimetic Synthetic Studies on the Bruceol Family of Meroterpenoid Natural Products
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A biomimetic approach to total synthesis can offer several benefits, including the development of cascade reactions for the rapid generation of molecular complexity, and guidance in the structure revision of old natural products and the anticipation of ne
- Day, Aaron J.,George, Jonathan H.,Sumby, Christopher J.
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- Palladium(II)-catalyzed efficient synthesis of wedelolactone and evaluation as potential tyrosinase inhibitor
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Tyrosinase is an enzyme widely distributed in nature, which has multiple functions, especially in the melanin biosynthesis pathway. Despite the few clinically available tyrosinase inhibitors for whitening, a great demand remains for novel compounds with low side effects in terms of potential carcinogenicity and improved clinical efficacy. A natural product, wedelolactone (WEL), with a polyhydroxyl moiety, attracted our attention as a potential tyrosinase inhibitor. Before we studied the biological activity of the natural product, a synthetic methodological research was firstly carried to obtain enough raw material. WEL could be obtained efficiently through palladium-catalyzed boronation/coupling reactions and 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ)-involved oxidative deprotection/annulation reactions. Immediately after, the natural product was proven to be an efficient tyrosinase inhibitor. In conclusion, we developed a mild and efficient approach for the preparation of WEL, and the natural product was disclosed to have anti-tyrosinase activity, which could be widely used in multiple fields.
- Huang, Huidan,Chen, Jianqiu,Ren, Jie,Zhang, Chaofeng,Ji, Fei
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- Structures of antimutagenic constituents in the peels of Citrus limon
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The methanolic extracts from the peels of Citrus limon were found to show antimutagenic effects against 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the Ames test. From the methanolic extracts, four new coumarins (wakayamalimonol A–D) and a new furanocoumarin (wakayamalimonol E) were isolated together with fifteen known compounds. The absolute stereostructures of the new compounds were determined by chemical synthesis and the modified Mosher’s method. Among the isolated constituents, coumarins, furanocoumarins, and limonoids showed antimutagenic effects in the Ames test. One of the major constituent, limonin, showed significant antimutagenic effects against mitomycinC and PhIP in the micronucleus test in vivo.
- Matsumoto, Takahiro,Takahashi, Kazuki,Kanayama, Sumire,Nakano, Yuka,Imai, Hiromi,Kibi, Masumi,Imahori, Daisuke,Hasei, Tomohiro,Watanabe, Tetsushi
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p. 735 - 744
(2017/09/29)
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- Difluoromethylthiolation of Phenols and Related Compounds with a HF2CSO2Na/Ph2PCl/Me3SiCl System
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A novel HF2CSO2Na/Ph2PCl/Me3SiCl system is disclosed for the late-stage direct difluoromethylthiolation of Csp2 and Csp3 nucleophiles. Difluoromethylthiolation of phenols and naphthols proceeded nicely under this system to regioselectively provide corresponding SCF2H compounds in good yields. Other substrates such as indoles, pyrroles, pyrazoles, enamines, ketones, and β-keto esters were also transformed to corresponding SCF2H products in good yields. The late-stage direct difluoromethylthiolation of a number of natural products and pharmaceutically attractive molecules was also achieved.
- Huang, Zhongyan,Matsubara, Okiya,Jia, Shichong,Tokunaga, Etsuko,Shibata, Norio
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supporting information
p. 934 - 937
(2017/02/26)
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- Ytterbium triflate promoted coupling of phenols and propiolic acids: Synthesis of coumarins
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Coumarins are a well-known class of natural occurring and semi-synthetic products with reported important and effective pharmacological activities. In this Letter an improved method for the chemical synthesis of such compounds is described. Coumarins have been obtained in good to excellent yields under microwave irradiation and solvent-free conditions in a short time from differently substituted phenols and propiolic acids used as starting materials in the presence of Yb(OTf)3 hydrate 10% mol as the catalyst.
- Fiorito, Serena,Epifano, Francesco,Taddeo, Vito A.,Genovese, Salvatore
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supporting information
p. 2939 - 2942
(2016/06/14)
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- A Total Synthesis of (±)-Rhododaurichromanic Acid A via an Oxa-[3+3] Annulation of Resorcinols
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Development of an oxa-[3+3] annulation of vinyliminium salts with resorcinols as a 1,3-diketo equivalent is described. This annulation constitutes a cascade of Knoevenagel condensation-oxa-electrocyclization leading to a direct access to chromenes. A series of attempts was made to demonstrate its synthetic utility in natural product synthesis, culminating in a total synthesis of (±)-rhododaurichromanic acid A that also featured an intramolecular Gassman-type cationic [2+2] cycloaddition.
- Luo, Guo-Ying,Wu, Hao,Tang, Yu,Li, Hui,Yeom, Hyun-Suk,Yang, Ka,Hsung, Richard P.
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p. 2713 - 2720
(2015/09/15)
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- Synthesis and cytotoxicity of coumarin derivatives and nordentatin
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Nordentatin and 10 coumarin derivatives were synthesized and evaluated for cytotoxicity. Compounds 6, 7, 9 and 13 showed cytotoxicity against the NCI-H187 cell line with IC50 value ranging of 3-7 μg/mL. Among synthesized coumarins, compounds 4 and 13 demonstrated cytotoxicity against the KB cell line with IC50 values of 3.94 and 6.44 μg/mL, respectively. Fortunately, coumarins 4 and 7 may be one of the new lead compounds for the development of anticancer agents due to reason that they showed weak and inactive against normal cells.
- Promsuwan, Pawantree,Yenjai, Chavi
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p. 3629 - 3632
(2013/05/09)
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- A catalyst-free one-pot construction of skeletons of 5-methoxyseselin and alloxanthoxyletin in water
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In refluxing water and without an additional catalyst, electron-rich phenols could react with alkynoic acids or alkynoates to provide coumarin structures. The skeletons of two natural pyranocoumarins, 5-methoxyseselin and alloxanthoxyletin, could be constructed (total yield up to 76%) in an aqueous multicomponent reaction in which isoprenyl acetate, propiolic acid, and phloroglucinol were simply mixed and refluxed in water.
- Cao, Jin-Li,Shen, Su-Li,Yang, Peng,Qu, Jin
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p. 3856 - 3859
(2013/09/02)
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- Improved synthesis of coumarins by iron(III)-catalyzed cascade reaction of propiolic acids and phenols
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The reaction of propiolic acids with phenols in the presence of FeClAgOTf catalyst proceeded efficiently in a mixed solvent of trifluoroacetic acid and 1,2-dichloroethane, and provided coumarins in good to high yields. This iron-catalyzed reaction offers a much-improved synthesis of coumarins. Thieme Stuttgart New York.
- Kutubi, Md. Shahajahan,Hashimoto, Takuya,Kitamura, Tsugio
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experimental part
p. 1283 - 1289
(2011/05/19)
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- Synthesis of coumarins and neoflavones through zinc chloride catalyzed hydroarylation of acetylenic esters with phenols
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Acetylenic esters react with oxygenated phenols under solvent-free conditions in the presence of only 5 mol% of zinc chloride as a catalyst to give coumarins and neoflavones in reasonable-to-good yields. Georg Thieme Verlag Stuttgart. New York.
- Leao, Raquel A. C.,Def.demoraes, Paula,Pedro, Marcella C. B. C.,Costa, Paulo R. R.
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experimental part
p. 3692 - 3696
(2011/12/16)
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- Photoconversion of o-hydroxycinnamates to coumarins and its application to fluorescence imaging
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(E)-o-Hydroxycinnamates were synthesized and their photochemical behavior was investigated in liquid and solid states. It was confirmed by 1H NMR spectroscopy that the (E)-o-hydroxycinnamates converted into the corresponding coumarins via (Z)-o-hydroxycinnamate intermediates. The photoconversion was greatly accelerated in the presence of p-toluenesulfonic acid. The optical properties of the cinnamates were compared with those of the corresponding coumarins. Fluorescence imaging was successfully accomplished by photoirradiation of PMMA films containing the cinnamates.
- Cho, Sung-Youl,Song, Young-Kyu,Kim, Joong-Gon,Oh, Se-Young,Chung, Chan-Moon
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supporting information; experimental part
p. 4769 - 4772
(2011/03/19)
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- Total synthesis of demethylwedelolactone and wedelolactone by Cu-mediated/Pd(0)-catalysis and oxidative-cyclization
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Hedysarimcoumestan B, which can be isolated from Chinese herbal medicine, is achieved, in which the longest linear sequence is only eight steps, in 50% overall yield from commercially available phloroglucinol. The key transformations in the synthesis are Cu-mediated/Pd(0)-catalysis and I2/pyridine oxidative-cyclization reactions. This synthetic strategy can be applied to give access to the demethylwedelolactone (4) and wedelolactone (5), which were afforded from commercially available phloroglucinol in high 38 and 33% yields, respectively.
- Chang, Chia-Fu,Yang, Ling-Yi,Chang, Shiao-Wei,Fang, Yu-Ting,Lee, Yean-Jang
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p. 3661 - 3666
(2008/09/20)
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- Nonacid cleavable detergents applied to MALDI mass spectrometry profiling of whole cells
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Although cleavable detergents were first synthesized a number of years ago, they have only recently been successfully applied to problems involving biological molecules. Recent reports have demonstrated that these compounds are useful for applications inv
- Norris, Jeremy L.,Hangauer, Matthew J.,Porter, Ned A.,Caprioli, Richard M.
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p. 1319 - 1326
(2007/10/03)
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- Natural and synthetic 2,2-dimethylpyranocoumarins with antibacterial activity
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A new efficient synthetic approach to the natural coumarins 5-hydroxyseselin (5), 5-methoxyseselin (3), and (±) cis-grandmarin (9) is described as well as the synthesis of some new derivatives in the 5-methoxyseselin series (10-15). The natural coumarins 7-hydroxyalloxanthyletin (6), alloxanthoxyletin (8), and dipetalolactone (7) have also been obtained as secondary products. The type of fusion of the pyrano ring in all cases has been established by 2D NMR spectroscopy. The compounds have been studied for their in vitro antibacterial activity, which has been compared with that of some previously synthesized seselin derivatives. The most active compounds were 3, 7, 8, 11, and 14. Some structure-activity relationships are discussed.
- Melliou, Eleni,Magiatis, Prokopios,Mitaku, Sofia,Skaltsounis, Alexios-Leandros,Chinou, Efrosini,Chinou, Ioanna
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- A single-step assembly of coumarin ring skeleton from oxygenated phenols and acetylenic esters by catalytic indium chloride in the absence of solvent
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Ring oxygenated coumarins were obtained in a single-step by condensation of appropriately substituted phenols with acetylenic esters by catalytic amounts of indium chloride in the absence of solvent.
- Kalyanam,Nagarajan,Majeed
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p. 1909 - 1914
(2007/10/03)
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- Atom economy. Palladium-catalyzed formation of coumarins by addition of phenols and alkynoates via a net C-H insertion
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A strategy to achieve ortho substitution of phenols initiated by an ortho-palladation to create coumarins was examined. Indeed, treatment of alkynoates with electron-rich phenols in the presence of a palladium catalyst and an acid does generate coumarins. The scope of the reaction with respect to the phenol and the alkynoates is defined. With unsymmetrical aromatic substrates, generally good regioselectivity that reflects the HOMO coefficients can be observed. In the course of these studies, numerous important naturally occurring coumarins have been synthesized, including fraxinol methyl ether, ayapin, herniarin, xanthoxyletin, and alloxanthoxyletin. The fact that a Pd(0) is the precatalyst rather than a Pd(+2) species and that an acid that reduces Pd(+2) salts, formic acid, functions better than other carboxylic acids raises doubts about the initial working hypothesis. A novel mechanism involving a palladium phenoxide formed from a hydridopalladium carboxylate and phenol is invoked to rationalize the results.
- Trost, Barry M.,Toste, F. Dean,Greenman, Kevin
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p. 4518 - 4526
(2007/10/03)
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- Alkoxypsoralens, novel nonpeptide blockers of Shaker-type K+ channels: Synthesis and photoreactivity
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A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8- Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1.3.
- Wulff, Heike,Rauer, Heiko,Düring, Tim,Hanselmann, Christine,Ruff, Katharina,Wrisch, Anja,Grissmer, Stephan,H?nsel, Wolfram
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p. 4542 - 4549
(2007/10/03)
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