- Synthesis, antitumor activity, and mechanism of action of 6-acrylic phenethyl ester-2-pyranone derivatives
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Based on the scaffolds of caffeic acid phenethyl ester (CAPE) as well as bioactive lactone-containing compounds, 6-acrylic phenethyl ester-2-pyranone derivatives were synthesized and evaluated against five tumor cell lines (HeLa, C6, MCF-7, A549, and HSC-2). Most of the new derivatives exhibited moderate to potent cytotoxic activity. Moreover, HeLa cell lines showed higher sensitivity to these compounds. In particular, compound 5o showed potent cytotoxic activity (IC50 = 0.50-3.45 μM) against the five cell lines. Further investigation on the mechanism of action showed that 5o induced apoptosis, arrested the cell cycle at G2/M phases in HeLa cells, and inhibited migration through disruption of the actin cytoskeleton. In addition, ADMET properties were also calculated in silico, and compound 5o showed good ADMET properties with good absorption, low hepatotoxicity, and good solubility, and thus, could easily be bound to carrier proteins, without inhibition of CYP2D6. A structure-activity relationship (SAR) analysis indicated that compounds with ortho-substitution on the benzene ring exhibited obviously increased cytotoxic potency. This study indicated that compound 5o is a promising compound as an antitumor agent.
- Fang, Sai,Chen, Lei,Yu, Miao,Cheng, Bao,Lin, Yongsheng,Morris-Natschke, Susan L.,Lee, Kuo-Hsiung,Gu, Qiong,Xu, Jun
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Read Online
- Regioselective functionalization of pyrones: Facile synthesis of 6-styrylpyrones via KHMDS-mediated aldol condensation
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Herein, we disclose our efforts directed toward the synthesis of the kavalactone-based natural product penstyrylpyrone and other related 4-OMe-2-pyrones possessing diverse substituents at the 3-, 5-, and 7-positions. Further, a facile approach to access 6-styrylpyrones via the KHMDS-mediated regioselective aldol condensation of 2-pyrones is described with moderate substrate scope and good to high yields (58–80%). The utility of this methodology was exemplified by the stereoselective construction of desmethoxyyangonin, asnipyrone A, and asnipyrone B.
- Basu, Manas K.,Mukkanti, K.,Samala, Ramakrishna
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supporting information
(2022/01/03)
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- Linderapyrone: A Wnt signal inhibitor isolated from Lindera umbellata
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Linderapyrone, a Wnt signal inhibitor was isolated from the methanolic extract of the stems and twigs of Lindera umbellata together with epi-(-)-linderol A. Linderapyrone inhibited TCF/β-catenin transcriptional activity that was evaluated using cell-based TOPFlash luciferase assay system. To evaluate the structure-activity relationship and mechanism, we synthesized linderapyrone and its derivatives from piperitone. As the results of further bioassay for synthesized compounds, we found both of pyrone and monoterpene moieties were necessary for inhibitory effect. cDNA microarray analysis in a linderapyrone derivative treated human colorectal cancer cells showed that this compound downregulates Wnt signaling pathway. Moreover, we successes to synthesize the derivative of linderapyrone that has stronger inhibitory effect than linderapyrone and ICG-001 (positive control).
- Matsumoto, Takahiro,Kitagawa, Takahiro,Imahori, Daisuke,Matsuzaki, Atsushi,Saito, Youhei,Ohta, Tomoe,Yoshida, Tatsusada,Nakayama, Yuji,Ashihara, Eishi,Watanabe, Tetsushi
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supporting information
(2021/06/07)
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- Biomimetic Total Synthesis of Enterocin
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The first chemical total synthesis of the highly oxygenated polyketide enterocin has been accomplished. The key step of the synthesis was a late-stage biomimetic reaction cascade involving two intramolecular aldol reactions in which each step proceeded in 52 % yield (averaged) and which established four of the seven stereogenic centers. The pivotal precursor for the cascade reaction was assembled from three readily available building blocks. A chiral dithioacetal with two stereogenic centers originating from L-arabinose represented the core fragment to both ends of which the other building blocks were attached by aldol reactions. The remaining stereogenic center was installed by Davis oxygenation immediately prior to the key step.
- Bach, Thorsten,Koser, Lilla,Lechner, Vivian Miles
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supporting information
p. 20269 - 20273
(2021/08/13)
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- Hispidine compound and application thereof
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The invention relates to the technical field of synthetic medicine, in particular to a hispidine compound and pharmaceutical salt thereof, and application to the aspect of treating and preventing obesity and hyperlipemia. The hispidine compound can obviously inhibit the accumulation of triglyceride and total fat in the 3T3-L1 preadipocyte differentiation process; the inhibition effect is superiorto that of a positive control compound of jamaicin; no obvious cytotoxicity exists. In addition, a beta-lactam hispidine compound can also regulate and control the phosphorylation of transcription factors AMPK and ACC of fat metabolism and the SIRT1 expression quantity, and can regulate and control the expression quantity of transcription factors PPAR-gamma, SREBP-1c and FABP4 of the adipocyte differentiation. Therefore the medicine containing the hispidine compound and/or the pharmaceutical salt has good effects of inhibiting the adipocyte differentiation and reducing oil drops and triglyceride in the adipocyte; good development prospects are realized in the aspects of treating or preventing obesity and reducing the blood fat.
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Paragraph 0039; 0043
(2018/03/25)
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- Design, syntheses and lipid accumulation inhibitory activities of novel resveratrol mimics
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Hispidine was initially discovered from Ficus Hispida for cardiovascular protection. In this paper, hispidine derivatives, which contain a novel resveratrol-like scaffold, have been designed, synthesized, and assayed as agents against lipid accumulations in 3T3-L1 pre-adipocytes. Six hispidine derivatives have the activity of reducing TG in 3T3-L1 adipocytes in dosage-dependent manner. The most active compound can reduce the lipid accumulation up to 78.4% at 10 μM qPCR and Western blotting results demonstrate that the two most active compounds inhibit both lipodenesis and adipogenesis in 3T3-L1 cells through (1) increasing the phosphorylations of AMPK and ACC, promoting SIRT1 expression. These three proteins are key regulators for lipogenesis and energy metabolism. (2) Decreasing the expressions of PPARγ, sREBP-1c, and FABP4, which are pivotal regulators for adipogenesis. Overall, this work proves that hispidine derivatives diminish the lipid accumulation in 3T3-L1 cell line by downregulating lipogenic and adipogenic pathways.
- Li, Chanjuan,Cheng, Bao,Fang, Sai,Zhou, Huihao,Gu, Qiong,Xu, Jun
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p. 114 - 122
(2017/11/27)
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- A caffeic acid phenyl ester compound and its preparation method and application
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The invention discloses caffeic acid phenethyl ester compounds. The compounds have a structure shown in the chemical general formula A or B, wherein R1 in the formula A is substituent group on one or more benzene ring; R1 is independently selected from H, alkyl, alkoxy, halogen, nitryl, phenyl or trimethyl halide; R2 in the formula B is independently selected from the following groups shown in the specification. The compounds disclosed by the invention have better inhibiting function for the proliferation of a plurality of human tumor cells, and the compounds can be used for preparing anti-tumor drugs; therefore, the compounds have very high medical value and wide market prospect. (The formulae A and B are shown in the specification).
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Paragraph 0028; 0029
(2017/08/25)
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- Synthesis of novel 5,6-dehydrokawain analogs as osteogenic inducers and their action mechanisms
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An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synthesized and evaluated series of 5,6-dehydrokawain analogs. Our structure-activity relationships revealed that alkylation of para or meta position of aromatic ring of 1 promote osteogenic activity. Among the potential analogs we synthesized, (E)-6-(4-Ethylstyryl)-4-methoxy-2H-pyran-2-one (14) and (E)-6-(4-Butylstyryl)-4-methoxy-2H-pyran-2-one (21) both significantly up-regulated Runx2 and Osterix mRNA expression at 10?μM. These osteogenic activities could be mediated by bone morphogenetic protein (BMP) and activation of p38 MAPK signaling pathways. Compounds 14 and 21 also inhibited RANKL-induced osteoclast differentiation of RAW264 cells. These results indicated that novel 5,6-dehydrokawain analogs not only increase osteogenic activity but also inhibit osteoclast differentiation, and could be potential lead compounds for the development of anti-osteoporosis agents.
- Kumagai, Momochika,Nishikawa, Keisuke,Mishima, Takashi,Yoshida, Izumi,Ide, Masahiro,Koizumi, Keiko,Nakamura, Munetomo,Morimoto, Yoshiki
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p. 2401 - 2406
(2017/05/09)
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- Easy and green synthesis of 6-(arylvinyl)-4-hydroxy-3-(phenylsulfanyl)-2H-pyran-2-ones in aqueous potassium hydroxide
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A convenient green procedure have been proposed for the synthesis of 6-(2-arylvinyl)-4-hydroxy-3-(phenylsulfanyl)-2H-pyran-2-ones by condensation of 6-(arylvinyl)-4-hydroxy-2H-pyran-2-ones with S-phenyl benzenesulfonothioate in aqueous potassium hydroxide at room temperature.
- Benferrah,Hammadi,Berthiol
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p. 2881 - 2886
(2017/03/22)
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- Potassium fluoride-barium oxide catalysis in an easy and efficient synthesis of methysticin from piperonal under microwave irradiation
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Condensation of compounds containing active methylene group with aromatic aldehyde (piperonal) in the presence of BaO on KF without a solvent under microwave irradiation is an efficient synthetic approach to methysticin and derivatives of kavalactones (4-methoxy-6-styryl-pyran-2-ones).
- Benferrah,Hammadi,Berthiol
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p. 1939 - 1944
(2015/10/12)
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- Synthesis and Anti-neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2-nitro-1-phenyl-1H-Indole Derivatives as p38α MAPK Inhibitors
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Inhibition of p38 mitogen-activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF-κB and p38α MAPK inhibitor 5,6-dehydrokawain and p38α MAPK inhibitors 1a, 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl)ureas, and 1b, a class of indole-pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2-nitro-1-phenyl-1H-indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)-induced microglia activation with IC50 less than the control 5,6-dehydrokawain. Notably, compound 27, 6-methoxy-2-nitro-1-(1H-1, 2, 3-triazol-1-yl)-1H-indole, with IC50 values of 1.6 μm can markedly inhibit p38α MAPK and NO release in BV-2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood-brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti-neuroinflammatory agents for AD. We designed, synthesized and evaluated two series lactone benzoyl hydrazine and 2-nitro-1-phenyl-1H-Indole derivatives for novel promising chemical lead p38α MAPK inhibitors as anti-neuroinflammatory agents in fighting against Alzheimer's diseases.
- Cheng, Bao,Lin, Yongsheng,Kuang, Ming,Fang, Sai,Gu, Qiong,Xu, Jun,Wang, Laiyou
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p. 1121 - 1130
(2015/10/28)
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- Heck-matsuda arylation as a strategy to access kavalactones isolated from polygala sabulosa, piper methysticum, and analogues
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Herein, we describe the total syntheses of three bioactive pyrones isolated from Polygala sabulosa (i.e., 1, 4, and 7) and eight isolated from Piper methysticum (i.e., 8-10, 13, 15, and 18-20) using the Heck-Matsuda arylation as the key strategy. The evaluation of this methodology by employing different arenediazonium tetrafluoroborates revealed that the Heck arylation was more efficient when the olefin undergoing arylation possessed the vinyl-2-pyrone structural unit instead of the vinyl dihydro-2-pyrone moiety. The Heck-Matsuda arylation of many of the examined olefins proceeded in a practical manner with total regio- and stereocontrol.
- Soldi, Cristian,Moro, Angelica V.,Pizzolatti, Moacir G.,Correia, Carlos R. D.
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p. 3607 - 3616
(2012/07/31)
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- Synthesis and biological evaluation of polyenylpyrrole derivatives as anticancer agents acting through caspases-dependent apoptosis
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A class of polyenylpyrroles and their analogues were designed from a hit compound identified in a fungus. The compounds synthesized were evaluated for their cell cytotoxicity against human non-small-cell lung carcinoma cell lines A549. Two compounds were found to exhibit high cytotoxicity against A549 cells with IC50 of 0.6 and 0.01 μM, respectively. The underlying mechanisms for the anticancer activity were demonstrated as caspases activation dependent apoptosis induction through loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein (Bax) level, and decrease in B-cell lymphoma-2 (Bcl-2) level. The two compounds were nontoxic to normal human lung Beas-2b cells (IC50 > 80 μM), indicating that they are highly selective in their cytotoxicity activities. Furthermore, one compound showed in vivo anticancer activity in human-lung-cancer-cell-bearing mice. These results open promising insights on how these conjugated polyenes mediate cytotoxicity and may provide a molecular rationale for future therapeutic interventions in carcinogenesis.
- Fang, Zhanxiong,Liao, Pei-Chun,Yang, Yu-Liang,Yang, Feng-Ling,Chen, Yi-Lin,Lam, Yulin,Hua, Kuo-Feng,Wu, Shih-Hsiung
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supporting information; experimental part
p. 7967 - 7978
(2011/03/19)
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- Synthesis of the pyranonaphthoquinones dehydroherbarin, (+)-astropaquinone B and (+)-astropaquinone C en route to ascomycones A and B
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The total syntheses of the pyranonaphthoquinone natural products dehydroherbarin, (+)-astropaquinone B and (+)-astropaquinone C are described. A late stage oxidation strategy employed for the synthesis of the astropaquinones was not amenable to the conversion of dehydroherbarin into the ascomycones. The syntheses of astropaquinones B and C reported herein constitute the first total syntheses and their absolute stereochemistry was determined to be (1R,3S). Georg Thieme Verlag Stuttgart New York.
- Wadsworth, Andrew D.,Sperry, Jonathan,Brimble, Margaret A.
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experimental part
p. 2604 - 2608
(2010/09/08)
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- SERINE HYDROLASE INHIBITORS
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Provided herein are benzoxazinone compounds of formula (I) and compositions containing the compounds. The compounds and compositions are useful in the methods of inhibiting the action of serine hydrolase, including neutrophil elastase. In certain embodiments, the compounds and compositions are useful in the prevention, amelioration or treatment of serine hydrolase-mediated diseases.
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Page/Page column 60-61
(2008/06/13)
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- Biosynthesis of phloroglucinol
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Substantial concentrations of phloroglucinol were synthesized by Pseudomonas fluorescens Pf-5 expressing the plasmid-localized phlACBDE gene cluster responsible for biosynthesis of 2,4-diacetylphloroglucinol. Expression in Escherichia coli of a single gene in this cluster, P. fluorescens Pf-5 phlD, led to extracellular accumulation of phloroglucinol. Purification of PhlD to homogeneity afforded an enzyme that catalyzed the conversion of malonyl-CoA into phloroglucinol with Km = 5.6 μM and kcat = 10 min-1. Acetylase and deacetylase activities were observed with the catalyzed interconversions of phloroglucinol, 2-acetylphloroglucinol, and 2,4-diacetylphloroglucinol when phlACB was expressed in E. coli. Beyond the mechanistic implications attendant with the identification of an enzyme that catalyzes the conversion of malonyl-CoA into phloroglucinol, PhlD provides the basis for environmentally benign syntheses of phloroglucinol and resorcinol from glucose. Copyright
- Achkar, Jihane,Xian, Mo,Zhao, Huimin,Frost
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p. 5332 - 5333
(2007/10/03)
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- Suzuki cross-coupling approaches to the synthesis of bioactive 3-substituted and 5-substituted-4-methoxy-6-methyl-2-pyrones
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Suzuki cross-coupling has been used to access a wide range of 3- and 5-substituted 2-pyrones, which show remarkable inhibitory activity against bacteria, yeasts and fungi. 3-Octenyl and 5-octenyl 2-pyrones inhibit human ovarium carcinoma (A2780) and human chronic myelogenous leukaemia (K562) cell lines at the micromolar level.
- Marrison, Lester R.,Dickinson, Julia M.,Fairlamb, Ian J.S.
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p. 2667 - 2671
(2007/10/03)
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- Deoxygenation of polyhydroxybenzenes: An alternative strategy for the benzene-free synthesis of aromatic chemicals
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New synthetic connections have been established between glucose and aromatic chemicals such as pyrogallol, hydroquinone, and resorcinol. The centerpiece of this approach is the removal of one oxygen atom from 1,2,3,4-tetrahydroxybenzene, hydroxyhydroquinone, and phloroglucinol methyl ether to form pyrogallol, hydroquinone, and resorcinol, respectively. Deoxygenations are accomplished by Rh-catalyzed hydrogenation of the starting polyhydroxybenzenes followed by acid-catalyzed dehydration of putative dihydro intermediates. Pyrogallol synthesis consists of converting glucose into myo-inositol, oxidation to myo-2-inosose, dehydration to 1,2,3,4-tetrahydroxybenzene, and deoxygenation to form pyrogallol. Synthesis of pyrogallol via myo-2-inosose requires 4 enzyme-catalyzed and 2 chemical steps. For comparison, synthesis of pyrogallol from glucose via gallic acid intermediacy and the shikimate pathway requires at least 20 enzyme-catalyzed steps. A new benzene-free synthesis of hydroquinone employs conversion of glucose into 2-deoxy-scyllo-inosose, dehydration of this inosose to hydroxyhydroquinone, and subsequent deoxygenation to form hydroquinone. Synthesis of hydroquinone via 2-deoxy-scyllo-inosose requires 2 enzyme-catalyzed and 2 chemical steps. By contrast, synthesis of hydroquinone using the shikimate pathway and intermediacy of quinic acid requires 18 enzyme-catalyzed steps and 1 chemical step. Methylation of triacetic acid lactone, cyclization, and regioselective deoxygenation of phloroglucinol methyl ether affords resorcinol. Given the ability to synthesize triacetic acid lactone from glucose, this constitutes the first benzene-free route for the synthesis of resorcinol. Copyright
- Hansen, Chad A.,Frost
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p. 5926 - 5927
(2007/10/03)
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- Total synthesis of (-)-solanapyrone A via enzymatic Diels-Alder reaction of prosolanapyrone
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The syntheses of prosolanapyrones I (6) and II (7) via the aldol reactions of pyrone and dienal segments have been achieved in five steps in 31% overall yield for 6 and seven steps in 5% overall yield for 7. An improved synthetic route starting from vinylpyrone 27 provided 7 in 11 steps in 12% overall yield. The enzymatic Diels-Alder reaction of 7 affords (-)- solanapyrone A (1) with high enantioselectivity and with good exo- selectivity, which is difficult to attain by chemical methods. In addition, a crude enzyme preparation from Alternaria solani has been used to perform a kinetic resolution of (±)-3.
- Oikawa, Hideaki,Kobayashi, Tomonori,Katayama, Kinya,Suzuki, Yuichi,Ichihara, Akitami
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p. 8748 - 8756
(2007/10/03)
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- Synthetic hispidin, a PKC inhibitor, is more cytotoxic toward cancer cells than normal cells in vitro
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The trypanocidal activity of naturally occurring 6-(3,4-dihydroxystyryl)-4-hydroxy-2-pyrone (hispidin) prompted us to examine its cytotoxic activity toward normal and cancerous cells in culture. Hispidin synthesized in our laboratory to a high degree of purity (checked by 1H and 13C NMR spectroscopy) was shown to be cytotoxic (between 10-3 mol/L and 10-7 mol/L) toward normal human MRC-5 fibroblasts, human cancerous keratinocytes (SCL-1 cell line), and human cancerous pancreatic duct cells (Capan-1 cell line). Interestingly, addition of hispidin in three successive doses (between 10-5 mol/L and 10-7 mol/L) led to a 100-fold increase in activity with an enhanced activity on cancer cells compared to normal cells (50%). Synthetic hispidin was found to inhibit isoform β of protein kinase C (IC50 of 2 x 10-6 mol/L), but not E. coli and placental type XV alkaline phosphatases. The enhanced activity of hispidin toward the cancerous cell lines is discussed.
- Gonindard,Bergonzi,Denier,Sergheraert,Klaebe,Chavant,Hollande
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p. 141 - 153
(2007/10/03)
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- FUNCTIONALIZATION OF 4-HYDROXY-6-METHYL-2-PYRONE AT C-5 THROUGH SIGMATROPIC REARRANGEMENTS OF ALLYLIC SULFONIUM YLIDES
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Functionalization at C-5 of the triacetic acid lactone methyl ester, 7, has been achieved by a transfer from the C-6 position.Thus, treatment of sulfides 12 with an excess of ethyl diazoacetate provides the pyrones 15 through sigmatropic rearrangements.
- March, P. de,Moreno-Manas, M.,Ripoll, I.
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p. 521 - 532
(2007/10/02)
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- Enol Ethers, XIV. Acylation of Keto Enol Ethers with Malonyl Dichloride - A New Synthesis of Phloroglucinols
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Phloroglucinols 4 and/or 4-hydroxy-2H-pyran-2-ones 5 are formed from keto enol ethers 1 and malonyl dichloride (2a) in high yields.Since the pyranones 5 can be smoothly converted into phloroglucinols, the reaction of 1 with 2a represents a new, facile synthetic route to phloroglucinols.The reaction proceeds via formation of a chloro carbonyl ketene 8 and its subsequent reaction with 1.The product ratio 4:5 is rationalized in terms of substituent effects in the enol ether substrate.
- Effenberger, Franz,Schoenwaelder, Karl-Heinz
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p. 3270 - 3279
(2007/10/02)
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