- Phenolic 1,3-diketones attenuate lipopolysaccharide-induced inflammatory response by an alternative magnesium-mediated mechanism
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Background and Purpose: Toll-like receptor 4 (TLR4) plays a key role in the induction of inflammatory responses both in peripheral organs and the CNS. Curcumin exerts anti-inflammatory functions by interfering with LPS-induced dimerization of TLR4–myeloid
- Zusso, Morena,Mercanti, Giulia,Belluti, Federica,Di Martino, Rita Maria Concetta,Pagetta, Andrea,Marinelli, Carla,Brun, Paola,Ragazzi, Eugenio,Lo, Rita,Stifani, Stefano,Giusti, Pietro,Moro, Stefano
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Read Online
- Method for artificially synthesizing curcumin and derivative thereof
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The invention discloses a method for artificially synthesizing curcumin and a derivative thereof. The method comprises the steps of adopting calcium acetylacetonate as a acetylacetone supply source, carrying out claisen-schmidt ester condensation reaction on the calcium acetylacetonate and a corresponding benzaldehyde derivative, and dehydrating under the catalysis of a dehydrating agent which is tributyl borate to obtain a product intermediate (I) which is curcumin calcium salt; then hydrolyzing the intermediate (I) through a one-pot method to obtain a crude product, and purifying the crude product so as to obtain the final product curcumin and the derivative thereof. Compared with a acetylacetone boric acid complex method, according to the method provided by the invention, the calcium acetylacetonate is used, so that active sites of acetylacetonate during a reaction process are more accurate and activated, the generation of by-products is reduced, and the yield of the curcumin and the derivative thereof is improved.
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Paragraph 0031; 0032; 0033; 0034
(2017/08/29)
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- Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors
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The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheime?s disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kin
- Di Martino, Rita Maria Concetta,De Simone, Angela,Andrisano, Vincenza,Bisignano, Paola,Bisi, Alessandra,Gobbi, Silvia,Rampa, Angela,Fato, Romana,Bergamini, Christian,Perez, Daniel I.,Martinez, Ana,Bottegoni, Giovanni,Cavalli, Andrea,Belluti, Federica
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p. 531 - 544
(2016/02/05)
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- Mechanochemical synthesis of 2,2-difluoro-4, 6-bis(β-styryl)-1,3,2-dioxaborines and their use in cyanide ion sensing
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The conversion of arylaldehydes to 1,7-diaryl-5-hydroxyhepta-1,4,6-trien-3-ones (curcuminoids) and the mechanochemical cyclization of these products to 2,2-difluoro-4,6-bis(β-styryl)-1,3,2-dioxaborines using BF3-Et2O are described. Investigation of the cyanide ion sensing ability of the 2,2-difluoro-4,6-bis(β-styryl)-1,3,2-dioxaborines, in relation to the substituent groups on the aryl ring, showed that a hydroxy susbstituent is required, preferably para to the intervening carbon bridge.
- Sherin, Daisy R.,Thomas, Sherin G.,Rajasekharan, Kallikat N.
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p. 381 - 385
(2015/12/24)
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- Structural basis for the one-pot formation of the diarylheptanoid scaffold by curcuminoid synthase from Oryza sativa
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Curcuminoid synthase (CUS) from Oryza sativa is a plant-specific type III polyketide synthase (PKS) that catalyzes the remarkable one-pot formation of the C6-C7-C6 diarylheptanoid scaffold of bis-demethoxycurcumin, by the condensation of two molecules of 4-coumaroyl-CoA and one molecule of malonyl-CoA. The crystal structure of O. sativa CUS was solved at 2.5-? resolution, which revealed a unique, downward expanding active-site architecture, previously unidentified in the known type III PKSs. The large active-site cavity is long enough to accommodate the two C 6-C3 coumaroyl units and one malonyl unit. Furthermore, the crystal structure indicated the presence of a putative nucleophilic water molecule, which forms hydrogen bond networks with Ser351-Asn142-H 2O-Tyr207- Glu202, neighboring the catalytic Cys174 at the active-site center. These observations suggest that CUS employs unique catalytic machinery for the one-pot formation of the C6-C7-C 6 scaffold. Thus, CUS utilizes the nucleophilic water to terminate the initial polyketide chain elongation at the diketide stage. Thioester bond cleavage of the enzyme-bound intermediate generates 4-coumaroyldiketide acid, which is then kept within the downward expanding pocket for subsequent decarboxylative condensation with the second 4-coumaroyl-CoA starter, to produce bisdemethoxycurcumin. The structure-based site-directed mutants, M265L and G274F, altered the substrate and product specificities to accept 4-hydroxyphenyl- propionyl-CoA as the starter to produce tetrahydrobisdemethoxy- curcumin. These findings not only provide a structural basis for the catalytic machinery of CUS but also suggest further strategies toward expanding the biosynthetic repertoire of the type III PKS enzymes.
- Morita, Hiroyuki,Wanibuchi, Kiyofumi,Nii, Hirohiko,Kato, Ryohei,Sugio, Shigetoshi,Abe, Ikuro
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experimental part
p. 19778 - 19783
(2011/09/20)
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- Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors
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Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed.
- Qiu, Xu,Liu, Zhong,Shao, Wei-Yan,Liu, Xing,Jing, Da-Ping,Yu, Yan-Jun,An, Lin-Kun,Huang, Shi-Liang,Bu, Xian-Zhang,Huang, Zhi-Shu,Gu, Lian-Quan
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p. 8035 - 8041
(2008/12/23)
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- Curcuminoids form reactive glucuronides in vitro
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Curcumin is of current interest because of its putative anti-inflammatory, anticarcinogenic, and anti-Alzheimer's activity, but its pharmacokinetic and metabolic fate is poorly understood. The present in vitro study has therefore been conducted on the glucuronidation of curcumin and its major phase I metabolite, hexahydro-curcumin, as well as of various natural and artificial analogs. The predominant glucuronide generated by rat and human liver microsomes from curcumin, hexahydro-curcumin, and other analogs with a phenolic hydroxyl group was a phenolic glucuronide according to LC-MS/MS analysis. However, a second glucuronide carrying the glucuronic acid moiety at the alcoholic hydroxyl group was formed from the same curcuminoids, but not hexahydro-curcuminoids, by human microsomes. Curcuminoids without a phenolic hydroxyl group gave rise to the aliphatic glucuronide only. The phenolic glucuronides of curcuminoids, but not of hexahydro-curcuminoids, were rather lipophilic and, in part, unstable in aqueous solution, their stability depending strongly on the type of aromatic substitution. The phenolic glucuronide of curcumin and of its natural congeners, but not the parent compounds, clearly inhibited the assembly of microtubule proteins under cell-free conditions, implying chemical reactivity of the glucuronides. These novel properties of the major phase II metabolites of curcuminoids deserve further investigation.
- Pfeiffer, Erika,Hoehle, Simone I.,Walch, Stephan G.,Riess, Alexander,Solyom, Aniko M.,Metzler, Manfred
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p. 538 - 544
(2008/02/09)
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- A comparative study on the antioxidant properties of tetrahydrocurcuminoids and curcuminoids
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Several curcuminoids and tetrahydrocurcuminoids (THCs), bearing various hydroxyl and/or methoxy groups on their benzene rings, have been synthesized to study their antioxidant and hydrogen donating capacities using the DPPH method at 25 °C in methanol. The results show that the tetrahydrocurcuminoids are in general much more efficient than their curcuminoid analogs if they include a phenol group in meta- or para-position of the linking chain and a neighboring phenol or methoxy group. This efficiency gain of THCs by comparison to curcuminoids was attributed to the presence of benzylic hydrogens involved in the oxidation process of these compounds and not to the beta-diketone moiety in the chain.
- Portes, Elise,Gardrat, Christian,Castellan, Alain
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p. 9092 - 9099
(2008/02/10)
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- Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver
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Curcumin and its natural congeners are of current interest because of their putative anti-inflammatory and anticarcinogenic activities, but knowledge about their metabolic fate is scant. In the present study conducted with precision-cut liver slices from
- Hoehle, Simone I.,Pfeiffer, Erika,Solyom, Aniko M.,Metzler, Manfred
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p. 756 - 764
(2007/10/03)
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- TPA-induced up-regulation of activator protein-1 can be inhibited or enhanced by analogs of the natural product curcumin
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The activator protein-1 (AP-1) family of transcription factors, including the most common member c-Jun-c-Fos, participates in regulation of expression of numerous genes involved in proliferation, apoptosis, and tumorigenesis in response to a wide array of stimuli including pro-inflammatory cytokines, growth factors, stress, and tumor promoters. A number of plant polyphenols including curcumin, a yellow compound in the spice turmeric, have been shown to inhibit the activation of AP-1. Curcumin is a polyphenolic dienone that is potentially reactive as a Michael acceptor and also is a strong anti-oxidant. Multiple activities reported for curcumin, including inhibition of the stress-induced activation of AP-1, have been suggested to involve the anti-oxidant properties of curcumin. In the present study, a library of analogs of curcumin was screened for activity against the TPA-induced activation of AP-1 using the Panomics AP-1 Reporter 293 stable cell line which is designed for screening potential inhibitors. Numerous analogs were identified that were more active than curcumin, including analogs that were not anti-oxidants and analogs that were not Michael acceptors. Clearly, anti-oxidant activity or reactivity as a Michael acceptor is not an essential feature of active compounds. In addition, a number of analogs were identified that enhanced the TPA-induced activation of AP-1. The results from screening were confirmed using BV-2 microglial cells where curcumin and analogs were shown to inhibit LPS-induced COX-2 expression; analogs identified as more potent than curcumin in the screening assay were also more potent than curcumin in preventing COX-2 expression.
- Weber, Waylon M.,Hunsaker, Lucy A.,Gonzales, Amanda M.,Heynekamp, Justin J.,Orlando, Robert A.,Deck, Lorraine M.,Vander Jagt, David L.
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p. 928 - 940
(2007/10/03)
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- Pharmaceutical compositions useful in prevention and treatment of beta-Amyloid protein-induced disease
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The invention provides methods for treating beta-Amyloid protein-induced disease, pharmaceutical compositions and compounds useful for the same, and the use of these compounds for the manufacture of a medicament for treating the same. More particularly, the invention relates to the use of natural product compounds isolated from turmeric, gingko biloba, and ginger, and synthetic chemical analogues thereof, for the treatment of a beta-Amyloid protein-induced disease.
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Page/Page column 19; sheet 3
(2008/06/13)
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- Synthesis of glycosylcurcuminoids.
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Condensation of glycosylated arylaldehyde with acetylacetone-B(2)O(3) complex gave a corresponding diglycosylcurcuminoid, and a similar reaction using a mixture of arylaldehyde and glycosylarylaldehyde gave an unsymmetrical monoglycosylcurcuminoid, both as boron-complexes. The boron was removed from the complexes by heating in methanol, thus achieving the synthesis of di- and mono-glycosylcurcuminoids.
- Mohri, Kunihiko,Watanabe, Yuhya,Yoshida, Yuki,Satoh, Mitsuru,Isobe, Kimiaki,Sugimoto, Naoki,Tsuda, Yoshisuke
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p. 1268 - 1272
(2007/10/03)
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- Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: Synthesis, biological evaluation, and molecular modeling
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Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran- 2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2,4- dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1,3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an 'accessory' region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.
- Artico, Marino,Santo, Roberte Di,Costi, Roberta,Novellino, Ettore,Greco, Giovanni,Massa, Silvio,Tramontano, Enzo,Marongiu, Maria E.,De Montis, Antonella,Colla, Paolo La
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p. 3948 - 3960
(2007/10/03)
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- Synthesis of some curcumin derivatives and their antiinflammatory activity
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Curcumin is not only a frequently used food additive, but it is also a well-known constituent of Indonesian traditional medicines.Several beneficial effects are ascribed to curcumin, eg, its antiinflammatory properties.In order to study the antiinflammatory activity, a series of curcumin derivatives were prepared and the inhibition of the carrageenin-induced oedema by these compounds was investigated.It appeared that the para hydroxy groups in curcumin are important for antiinflammatory activity.This activity is enhanced when, in combination with the para hydroxy groups, the meta positions ore accupied with alkyl groups.Since the methyl derivatives are more active than the corresponding ethyl and tert-butyl derivatives, it is suggested that sterical hindrance is involved. - Keywords: curcumin/ antiinflammatory activity/ carrageenin-induced oedenoma.
- Nurfina, A. N.,Reksohadiprodjo, M. S.,Timmerman, H.,Jenie, U. A.,Sugiyanto, D.,Goot, H. van der
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p. 320 - 328
(2007/10/03)
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- Synthesis of Naturally Occuring Curcuminoids and Related Compounds
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Six known naturally occuring curcuminoids like curcumin, and 31 other analogs (Scheme 1) have been synthesized.Among them, 25 curcuminoids were prepared by condensing different substituted 2,4-pentanediones and benzaldehydes.The boron complex 12 has been used to avoid Knoevenagel condensation at C-3 of 2,4-pentanedione.Some curcuminoids containing hydroxy groups in the aromatic moiety have been acylated.Alkylation of the tetrabutylammonium salt of 5-hydroxy-1,7-diphenyl-1,4,6-heptatrien-3-one (1a) by benzyl bromide gave only C-alkylated 4-benzyl-1,7-diphenyl-1,6-heptadiene-3,5-dione (1d*).The 13C NMR data, the UV absorptions, and the tautomerism of the curcuminoids are discussed.
- Pedersen, Uffe,Rasmussen, Preben B.,Lawesson, Sven-Olov
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p. 1557 - 1569
(2007/10/02)
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