- BIFLORIN, A CHROMONE-C-GLUCOSIDE FROM PANCRATIUM BIFLORUM
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A new polyoxigenated chromone-C-glucoside, named biflorin, was isolated from the roots of Pancratium biflorum collected at flowering time.The structure of the compound was established as 5,7-dihydroxy-2-methylchromone-C6-β-D-glucopyranoside on the basis of comprehensive spectral analysis (UV, IR, 1H NMR, MS, D) and crucial chemical transformations of the compound and its derivatives.The biochemical significance of the occurence and ontogenic variations of biflorin and other polyoxygenated chromones in the title species is discussed.Key Word Index - Pancratium biflorum; Amaryllidaceae; roots; chromone-C-glucoside; biflorin; 5,7-dihydroxy-2-methylchromone-C6-β-D-glucopyranoside; chromone-metal ion complex; phosphodiesterase inhibitor.
- Ghosal, Shibnath,Kumar, Yatendra,Singh, Shripati, Ahad, Kamal
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- A plant type III polyketide synthase that produces pentaketide chromone
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A novel plant-specific type III polyketide synthase (PKS) that catalyzes formation of a pentaketide chromone, 5,7-dihydroxy-2-methylchromone, from five molecules of malonyl-CoA, was cloned and sequenced from aloe (Aloe arborescens). Site-directed mutagenesis revealed that Met207 (corresponding to Thr197 in CHS) determines the polyketide chain length and the product specificity of the enzyme; remarkably, replacement of a single amino acid residue, Met207, with Gly yielded a mutant enzyme that efficiently produces aromatic octaketides, SEK4 and SEK4b, the products of the minimal PKS for actinorhodin (act from Streptomyces coelicolor), from eight molecules of malonyl-CoA. This provided new insights into the catalytic functions and specificities of the CHS-superfamily type III PKS enzymes. Copyright
- Abe, Ikuro,Utsumi, Yoriko,Oguro, Satoshi,Morita, Hiroyuki,Sano, Yukie,Noguchi, Hiroshi
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- Engineered biosynthesis of plant polyketides: Manipulation of chalcone synthase
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Chalcone synthase (CHS) is a plant-specific type III polyketide synthase catalyzing condensation of 4-coumaroyl-CoA with three molecules of malonyl-CoA. Surprisingly, it was demonstrated that S338V mutant of Scutellaria baicalensis CHS produced octaketides SEK4/SEK4b from eight molecules of malonyl-CoA. Further, the octaketides-forming activity was dramatically increased in a CHS triple mutant (T197G/G256L/ S338T). The functional conversion is based on the simple steric modulation of a chemically inert residue lining the active-site cavity.
- Abe, Ikuro,Watanabe, Tatsuya,Morita, Hiroyuki,Kohno, Toshiyuki,Noguchi, Hiroshi
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- Engineered biosynthesis of plant polyketides: Chain length control in an octaketide-producing plant type III polyketide synthase
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The chalcone synthase (CHS) superfamily of type III polyketide syntheses (PKSs) produces a variety of plant secondary metabolites with remarkable structural diversity and biological activities (e.g., chalcones, stilbenes, benzophenones, acrydones, phloroglucinols, resorcinols, pyrones, and chromones). Here we describe an octaketide-producing novel plant-specific type III PKS from aloe (Aloe arborescens) sharing 50-60% amino acid sequence identity with other plant CHS-superfamily enzymes. A recombinant enzyme expressed in Escherichia coli catalyzed seven successive decarboxylative condensations of malonyl-CoA to yield aromatic octaketides SEK4 and SEK4b, the longest polyketides known to be synthesized by the structurally simple type III PKS. Surprisingly, site-directed mutagenesis revealed that a single residue Gly207 (corresponding to the CHS's active site Thr197) determines the polyketide chain length and product specificity. Small-to-large substitutions (G207A, G207T, G207M, G207L, G207F, and G207W) resulted in loss of the octaketide-forming activity and concomitant formation of shorter chain length polyketides (from triketide to heptaketide) including a pentaketide chromone, 2,7-dihydroxy-5-methylchromone, and a hexaketide pyrone, 6-(2,4-dihydroxy-6-methylphenyl)-4-hydroxy-2-pyrone, depending on the size of the side chain. Notably, the functional diversity of the type III PKS was shown to evolve from simple steric modulation of the chemically inert single residue lining the active-site cavity accompanied by conservation of the Cys-His-Asn catalytic triad. This provided novel strategies for the engineered biosynthesis of pharmaceutically important plant polyketides.
- Abe, Ikuro,Oguro, Satoshi,Utsumi, Yoriko,Sano, Yukie,Noguchi, Hiroshi
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- TMSI-Promoted vinylogous michael addition of siloxyfuran to 2-substituted chromones: A general approach for the total synthesis of chromanone lactone natural products
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A concise and facile synthetic protocol for the construction of the 2-γ-lactone chromanone skeleton has been achieved through a TMSI-promoted diastereoselective vinylogous Michael addition of siloxyfuran to 2-substituted chromones. The applicability of this method is demonstrated through the rapid access to the total syntheses of (±)-microdiplodiasone, (±)-lachnone C, and (±)-gonytolides C and G.
- Liu, Jie,Li, Zhanchao,Tong, Pei,Xie, Zhixiang,Zhang, Yuan,Li, Ying
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- Anti-inflammatory chromone alkaloids and glycoside from Dysoxylum binectariferum
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Herein we report isolation of a new chromone alkaloid chrotacumine K (12) from fruits and a chromone glycoside schumaniofioside A (13) from leaves of Dysoxylum binectariferum Hook f. Schumaniofioside A is reported for the first time from Meliaceae family. Other known alkaloids isolated include rohitukine (1) and chrotacumine E (6). The structure of new alkaloid 12 was elucidated on the basis of extensive 1D and 2D NMR analysis, synthesis and chemical hydrolysis. Chemically, chrotacumine K (12) is a 3′-O-acetyl rohitukine which on chemical or enzymatic hydrolysis produces rohitukine. The new alkaloid 12 is also present in seeds and stem-barks of this plant. The glycoside schumaniofioside A (13) is present only in leaves, and in abundance (~1% w/w of dried leaves). The isolated compounds and extracts were evaluated for in vitro effect on the proinflammatory cytokines (TNF-α and IL-6) in human monocytic THP-1 cells. The alkaloid 12 displayed potent inhibition (57%) of TNF-α at 0.3 μM, and was non-toxic to THP-1 cells up to 40 μM, indicating its excellent therapeutic window. Furthermore, a nitrobenzoyl ester analog 15e showed better inhibition of IL-6 than parent natural product chrotacumine K.
- Kumar, Vikas,Gupta, Mehak,Gandhi, Sumit G.,Bharate, Sonali S.,Kumar, Ajay,Vishwakarma, Ram A.,Bharate, Sandip B.
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- Structure-based engineering of a plant type III polyketide synthase: Formation of an unnatural nonaketide naphthopyrone
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Pentaketide chromone synthase (PCS) from Aloe arborescens is a novel plant-specific type III polyketide synthase (PKS) that produces 5,7-dihydroxy-2-methylchromone from five molecules of malonyl-CoA. On the basis of the crystal structures of wild-type and M207G mutant PCS, the F80A/Y82A/M207G triple mutant was constructed and shown to produce an unnatural novel nonaketide naphthopyrone by sequential condensations of nine molecules of malonyl-CoA. This is the first demonstration of the formation of a nonaketide by the structurally simple type III PKS. A homology model predicted that the active-site cavity volume of the triple mutant is increased to 4 times that of the wild-type PCS.
- Abe, Ikuro,Morita, Hiroyuki,Oguro, Satoshi,Noma, Hisashi,Wanibuchi, Kiyofumi,Kawahara, Nobuo,Goda, Yukihiro,Noguchi, Hiroshi,Kohno, Toshiyuki
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- CHROMONE GLYCOSIDES DROM SCHUMANNIOPHYTON MAGNIFICUM
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Two new chromone glycosides, schumanniofiosides A and B have been isolated from the root bark of Schumanniophython magnificum and their structures shown to be 2-methyl-5,7-dihydroxychromone 5-O-β-D-glucopyranoside and 2-methyl-5,7-dihydroxychromone 7-O-β-D-glocopyranosyl-(1 2)-apiofuranoside, respectively.The structures were elucidated by a combination of spectral data and chemical degradation.
- Tane, Pierre,Ayafor, Johnson F.,Sondengam, B. Luc,Connolly, Joseph D.
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- Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance
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The evolution and growth of multiple-herbicide resistance (MHR) in grass weeds continues to threaten global cereal production. While various processes can contribute to resistance, earlier work has identified the phi class glutathione-S-transferase (AmGSTF1) as a functional biomarker of MHR in black-grass (Alopecurus myosuroides). This study provides further insights into the role of AmGSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type AmGSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the AmGSTF1 inhibitor 4-chloro-7-nitro-benzofurazan (NBD-Cl) were obtained. These studies demonstrated that the inhibitory activity of NBD-Cl was associated with the occlusion of the active site and the impediment of substrate binding. A search for other selective inhibitors of AmGSTF1, using ligand-fishing experiments, identified a number of flavonoids as potential ligands. Subsequent experiments using black-grass extracts discovered a specific flavonoid as a natural ligand of the recombinant enzyme. A series of related synthetic flavonoids was prepared and their binding to AmGSTF1 was investigated showing a high affinity for derivatives bearing a O-5-decyl-α-carboxylate. Molecular modelling based on high-resolution crystal structures allowed a binding pose to be defined which explained flavonoid binding specificity. Crucially, high binding affinity was linked to a reversal of the herbicide resistance phenotype in MHR black-grass. Collectively, these results present a nature-inspired new lead for the development of herbicide synergists to counteract MHR in weeds. This journal is
- Brazier-Hicks, Melissa,Coxon, Christopher R.,Cummins, Ian,Edwards, Robert,Eno, Rebecca F. M.,Freitag-Pohl, Stefanie,Hughes, David J.,Mitchell, Glynn,Moore, Jenny,Onkokesung, Nawaporn,Pohl, Ehmke,Schwarz, Maria,Steel, Patrick G.,Straker, Hannah E.,Wortley, David J.
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supporting information
p. 9211 - 9222
(2021/11/16)
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- Synthesis and Antifungal Activity of Chromones and Benzoxepines from the Leaves of Ptaeroxylon obliquum
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This study reports the first total synthesis of the bioactive oxepinochromones 12-O-acetyleranthin (8) (angular isomer) and 12-O-acetylptaeroxylinol (9) (linear isomer). The antifungal activity of these compounds and their derivatives was determined against Candida albicans and Cryptococcus neoformans. Most compounds had good selectivity between the two fungi and showed moderate to good activity. 12-O-Acetyleranthin (8) had the highest activity against C. albicans, with an MIC value of 9.9 μM, while 12-O-acetylptaeroxylinol (9), the compound present in Ptaeroxylon obliquum, had the highest activity against C. neoformans, with an MIC value of 4.9 μM.
- Malefo, Modibo S.,Ramadwa, Thanyani E.,Famuyide, Ibukun M.,McGaw, Lyndy J.,Eloff, Jacobus N.,Sonopo, Molahlehi S.,Selepe, Mamoalosi A.
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p. 2508 - 2517
(2020/09/15)
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- Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis
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This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pHIB) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pHIB to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pKa value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pHIB, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.
- Wu, Jie,Mu, Ran,Sun, Mingna,Zhao, Nan,Pan, Miaomiao,Li, Hongshuang,Dong, Yi,Sun, Zhaogang,Bai, Jie,Hu, Minwan,Nathan, Carl F.,Javid, Babak,Liu, Gang
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p. 1087 - 1104
(2019/05/22)
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- Novel diphenylmethyl compounds having mycobacterium tuberculosis inhibitory activity
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The invention relates to novel diphenylmethyl derivatives having mycobacterium tuberculosis inhibitory activity and a preparation method thereof and particularly relates novel diphenylmethyl derivatives having activity for inhibiting replicative and non-replicating mycobacterium tuberculosis and a preparation method thereof. In particular, the invention relates to compounds shown in the formula (I) or all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein the variables are as described in the specification. The invention also relates to the preparation method of the compounds and their pharmaceutical compositions and a use of the compounds in preparation of drugs for treating mycobacterium tuberculosis infection-caused diseases.
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Paragraph 0845; 0846; 0849; 0850
(2019/02/13)
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- CHROMENONE INHIBITORS OF MONOCARBOXYLATE TRANSPORTERS
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The invention provides compounds effective as inhibitors of monocarboxylate transporters such as MCT1 and MCT4, which can be used for treatment of medical conditions wherein treatment of the condition with a compound having an inhibitor effect on MCT1, MC
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Page/Page column 28
(2016/08/17)
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- Compound 2-methyl -5,7-dihydroxy chromon a chemical preparation method
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The invention provides a chemical preparation method of a compound 2-methyl-5,7-dihydroxy chromone. The chemical preparation method comprises the following steps: by mainly adopting phloroglucinol and acetyl chloride as raw materials, firstly synthesizing 2,4,6-trihydroxy acetophenone by using Lewis acid as a catalyst in an organic solvent system; then replenishing acetyl chloride and a condensation catalyst namely anhydrous sodium acetate, further performing condensation with generated 2,4,6-trihydroxy acetophenone, and performing 'one-pot reaction' to obtain 2-methyl-3-acetyl-5,7-diacetoxyl chromone; and finally, removing acetyl and acetoxyl of 2-methyl-3-acetyl-5,7-diacetoxyl chromone by virtue of soda boiling to obtain a target product namely 2-methyl-5,7-dihydroxy chromone. The method provided by the invention is simple and easily-available in adopted raw material, can simplify the reaction steps, and has the advantages of low cost, high yield, mild reaction condition, applicability in industrial production, environmental protection and the like.
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Paragraph 0052; 0053; 0058; 0059
(2017/03/08)
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- Concise synthesis of 5-methoxy-6-hydroxy-2-methylchromone-7-O- and 5-hydroxy-2-methylchromone-7-O-rutinosides. Investigation of their cytotoxic activities against several human tumor cell lines
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The synthesis of two novel 2-methylchromone-7-O-rutinosides is reported, and the in vitro biological activities of these compounds and their synthetic precursors have been investigated on the basis of their cytotoxicity against several human tumor cell lines. The synthesis features early stage assembly of the acidic labile glycosidic bond between sugar and 2-methylchromone aglycon under phase transfer catalyzed glycosidation conditions, whereas all the other standard glycosylation conditions specific to a wide array of rutinosyl donors bearing different anomeric leaving groups (e.g., SPh, OC(NH)CCl3, Br, OH groups) failed to furnish any detectable products.
- Wu, Baolin,Zhang, Wenpeng,Li, Zhonghua,Gu, Li,Wang, Xin,Wang, Peng George
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scheme or table
p. 2265 - 2268
(2011/06/11)
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- Synthesis of the oxepinochromone natural products ptaeroxylin (desoxykarenin), ptaeroxylinol, and eranthin
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(Chemical Equation Presented) An improved synthesis of the oxepinochromone ptaeroxylin is reported, together with the syntheses of the related natural products ptaeroxylinol and eranthin. Ptaeroxylin and ptaeroxylinol were obtained from the chromenone nor
- Bruder, Marjorie,Haseler, Paul L.,Muscarella, Marina,Lewis, William,Moody, Christopher J.
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experimental part
p. 353 - 358
(2010/03/30)
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- Synthesis and structure-activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity
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Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions.
- Morita, Hiroshi,Tomizawa, Yuichiro,Deguchi, Jun,Ishikawa, Tokio,Arai, Hiroko,Zaima, Kazumasa,Hosoya, Takahiro,Hirasawa, Yusuke,Matsumoto, Takayuki,Kamata, Katsuo,Ekasari, Wiwied,Widyawaruyanti, Aty,Wahyuni, Tutik Sri,Zaini, Noor Cholies,Honda, Toshio
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experimental part
p. 8234 - 8240
(2010/03/25)
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- Chromone complexes
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The invention relates to complexes of certain chromone derivatives, to compositions which comprise such derivatives, to corresponding processes for the preparation of the chromone derivatives or of compositions comprising same, and to the use thereof, in particular for the care, maintenance or improvement of the general state of the skin or hair.
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- CHROMONE COMPLEXES
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The invention relates to complexes of certain chromone derivatives, preparations containing such derivatives, corresponding methods for producing chromone derivatives or preparations containing the same, and to the use thereof, especially for skin or hair care and for preserving or improving the general condition of the skin or hair.
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(2010/02/14)
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- Importance of the B ring and its substitution on the α-glucosidase inhibitory activity of baicalein, 5,6,7-trihydroxyflavone
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Hydroxychroniones and B-ring-substituted 5,6,7-trihydroxyflavones were prepared to evaluate the contribution of the B ring of baicalein (5,6,7-trihydroxyflavone, 1) to its potent α-glucosidase inhibitory activity. Hydroxychromones, which lack 6-hydroxyl substitution, did not show any inhibitory activity, while 5,6,7-trihydroxy-2-methylchromone (5) showed high activity. Among the tested B-ring-substituted 5,6,7-trihydroxyflavones, the 4′-hydroxy-, 3′,4′-dihydroxy-, and 3′,4′,5′- trihydroxy-substituted derivatives were found to give more activity than that of 1. The methoxy-substituted derivatives, however, showed less activity than 1. The results suggest that the B ring of 1 was not essential, although advantageous to the activity; hydroxyl substitution on the B ring of 5,6,7-trihydroxyflavones was favorable to the activity, whereas methoxyl substitution was unfavorable; at least 4′-hydrosyl substitution of 5,6,7-trihydroxyflavones was required for enhanced activity, in which the number of hydroxyl groups did not take part.
- Gao, Hong,Kawabata, Jun
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p. 1858 - 1864
(2007/10/03)
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- SYNTHESE DE TRIHYDROXYPHENACYLIDENETRIPHENYLPHOSPHORANES UNE NOUVELLE VOIE D'ACCES AUX DIHYDROXYFLAVONES (CHRYSINE, ACACETINE...)
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An easy and convenient synthesys of two new trihydroxyphenacylidenetriphenylphosphoranes from phloroglucinol and pyrogallol is described.Some dihydroxyflavones are prepared by acylation of these ylids, intramolecular olefination and saponification of the two remaining ester groups.
- Le Floc'H, Yves,Lefeuvre, Martine
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p. 5503 - 5504
(2007/10/02)
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- Biosynthesis of Aspyrone, a Metabolite of Aspergillus melleus. Incorporation Studies with 14C- and 3H-Labelled Acetates and Malonate
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Incorporation studies with 14C-labelled acetates and malonate confirm the polyketide origin of aspyrone (1), and identify the chain starter unit.Five carbons are derived from the methyl group of acetate, and the remaining four from the carboxy group.The pattern of incorporation of tritium from acetate is inconsistent with a biosynthesis from aromatic precursors of the mellein type.Possibly advanced precursors containing a 2-methylchromone nucleus were not incorporated.The evidence suggests that aromatic precursors are not involved in aspyrone biosynthesis, and that the carbon skeleton is produced like that of the co-metabolite asperlactone (6), by decarboxylation and rearrangement of a linear pentaketide intermediate.
- Copeland, R. Jeffrey,Hill, Robert A.,Hinchcliffe, David J.,Staunton, James
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p. 1013 - 1019
(2007/10/02)
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