- Neuroprotective effects of Tetrahydrocurcumin against glutamate-induced oxidative stress in hippocampal HT22 cells
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In the central nervous system, glutamate is a major excitable neurotransmitter responsible for many cellular functions. However, excessive levels of glutamate induce neuronal cell death via oxidative stress during acute brain injuries as well as chronic neurodegenerative diseases. The present study was conducted to examine the effect of tetrahydrocurcumin (THC), a major secondary metabolite of curcumin, and its possible mechanism against glutamate-induced cell death. We prepared THC using curcumin isolated from Curcuma longa (turmeric) and demonstrated the protective effect of THC against glutamate-induced oxidative stress in HT22 cells. THC abrogated glutamate-induced HT22 cell death and showed a strong antioxidant effect. THC also significantly reduced intracellular calcium ion increased by glutamate. Additionally, THC significantly reduced the accumulation of intracellular oxidative stress induced by glutamate. Furthermore, THC significantly diminished apoptotic cell death indicated by annexin V-positive in HT22 cells. Western blot analysis indicated that the phosphorylation of mitogen-activated protein kinases including c-Jun N-terminal kinase, extracellular signal-related kinases 1/2, and p38 by glutamate was significantly diminished by treatment with THC. In conclusion, THC is a potent neuroprotectant against glutamate-induced neuronal cell death by inhibiting the accumulation of oxidative stress and phosphorylation of mitogen-activated protein kinases.
- Park, Chang-Hyun,Song, Ji Hoon,Kim, Su-Nam,Lee, Ji Hwan,Lee, Hae-Jeung,Kang, Ki Sung,Lim, Hyung-Ho
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Read Online
- Structural and Biochemical Characterization of the Curcumin-Reducing Activity of CurA from Vibrio vulnificus
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Curcumin is a yellow-colored ingredient in dietary spice turmeric (Curcuma longa Linn). This nontoxic polyphenol has antitumor, anti-inflammatory, apoptotic, and antioxidant activities. The ingested curcumin is reduced to multihydrated forms with more potent therapeutic potentials by the curcumin reductase (CurA) from commensal Escherichia coli. In this study, we demonstrated that Vibrio vulnificus CurA (VvCurA) with 87% sequence similarity to the E. coli CurA exhibits the curcumin-reducing activity through spectrophotometric detection of NADPH oxidation and high performance liquid chromatographic analysis of curcumin consumption and product generation. Afterward, we determined the crystal structures of VvCurA and the VvCurA/NADPH complex, and made the in silico model of the VvCurA/NADPH/curcumin ternary complex through induced fit docking. Based on structural information, active site residues that play critical roles in catalysis have been identified and characterized by mutational and kinetic studies, leading us to propose the reaction mechanism of CurA.
- Park, Soo-Bong,Bae, Da-Woon,Clavio, Nina Abigail B.,Zhao, Lei,Jeong, Chang-Sook,Choi, Bo Mee,Macalino, Stephani Joy Y.,Cha, Hee-Jeong,Park, Jin-Byung,Lee, Jun Hyuck,Nam, Sang-Jip,Choi, Sun,Kim, Min-Kyu,Cha, Sun-Shin
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Read Online
- NOVEL TETRAHYDROCURCUMIN COMPOSITIONS, METHODS OF MAKING, AND METHODS OF USING THE SAME
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The present invention relates to novel tetrahydrocurcumin (THCu) compositions, novel methods of manufacturing, and methods of using these compositions for therapeutic applications. The novel synthetic pathway(s) result in THCu compositions that generally lack hexahydrocurcumin (HHC), and include an improved impurity profile with reduced additional species that are generally present in hydrogenated curcumin compositions.
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- Pharmacokinetics-driven evaluation of the antioxidant activity of curcuminoids and their major reduced metabolites—a medicinal chemistry approach
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Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism.
- ?tv?s, Sándor B.,Balogh, Gy?rgy T.,Fül?p, Ferenc,Girst, Gábor,Hunyadi, Attila
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- Preparation method of tetrahydrocurcumin and intermediate thereof
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The invention provides a preparation method of tetrahydrocurcumin and an intermediate thereof, and the preparation method of the intermediate comprises the following steps: step a, in the presence ofalkali, reacting a compound (IV) with an acetylation reagent in a solvent to obtain a compound (III); b, in the presence of a catalyst and a solvent, the compound (III) and hydrogen or a hydrogen donor are subjected to a reduction reaction to obtain a compound (II), namely the tetrahydrocurcumin intermediate; and the tetrahydrocurcumin preparation method comprises the step that acetyl is removed from the compound (II) in the solvent in the presence of alkali to obtain a compound (I), namely tetrahydrocurcumin. The selectivity of the diacetyl curcumin reduction reaction is far superior to thatof direct reduction of curcumin, and the yield is high; the method is simple and convenient in purification and high in product content, and hardly contains curcumin, hexahydrocurcumin and octahydrocurcumin; the method disclosed by the invention is simple and feasible to operate, stable and durable in process, easy to control, easy to amplify and convenient in post-reaction treatment, and can be economically and conveniently used for industrial production.
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Paragraph 0068-0085
(2020/05/01)
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- New insights towards 1,4-benzodiazepines from curcumin. Design, synthesis and antimicrobial activities
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Background: Curcumin is a safe, versatile natural product with unlimited number of biological activities and a precursor for various heterocyclic compounds. Objective: The present study was aimed to the development of a curcumin based antimicrobial reagent with high potency against gram-positive and gram-negative bacteria. Methods: Herein we report a simple and convenient one step method for synthesizing a series of 1,4-benzodiazepines via condensation cyclization reaction between curcumin and various 1,2- phenylenediamine in refluxed ethanol. Results: A series of new 1,4-benzodiazepins were synthesized and their structures were supported by FT-IR, 1H NMR, 13C NMR, and mass spectral analysis. Synthesized 1,4-benzodiazepins were evaluated for their in vitro antimicrobial activity against gram positive (S. aureus and S. epidermidis) and gram negative (E. coli and P. aeruginosa) bacteria. They exhibited low to high potency against the tested organisms. In particular, dichlorinated 1,4-benzodiazepine 9 exhibited a remarkable potency against the gram-positive bacteria S. aureus (MIC: 3.125 μg mL?1, MBC: 12 μg mL?1). It showed a higher potency than most of the tested reference drugs. Compound 9 showed the medium activity against E. Coli. Genotoxic study revealed that, benzodiazepines 9 attacked the DNA of E. Coli strains and damaged it. The potency of compound 9, could be attributed to the multiple chlorine atoms present on the aromatic ring. Conclusion: Some of the synthesized curcumin based benzodiazepines showed excellent potency against gram positive bacteria. These benzodiazepines could be a great candidate as a future antimicrobial agent.
- Hamed, Othman,Fares, Oswa,Taleeb, Shaima,Adwan, Ghaleb,Saadeh, Haythem,Jodeh, Shehdeh,Algarra, Manuel
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p. 1112 - 1123
(2020/11/09)
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- NOVEL TETRAHYDROCURCUMIN COMPOSITIONS, METHODS OF MAKING, AND METHODS OF USING THE SAME
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The present invention relates to novel tetrahydrocurcumin (THCu) compositions, novel methods of manufacturing, and methods of using these compositions for therapeutic applications. The novel synthetic pathway(s) result in THCu compositions that generally lack hexahydrocurcumin (HHC), and include an improved impurity profile with reduced additional species that are generally present in hydrogenated curcumin compositions.
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Paragraph 0023; 0029
(2020/09/19)
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- Novel preparation method for tetrahydrocurcumin
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The invention provides a novel preparation method for tetrahydrocurcumin. Curcumin, 2,6-dimethyl-3,5-diethyl ester-1,4-dihydropyridine (dihydropyridine for short) and ethanol are used as raw materials, and palladium on carbon is used as a catalyst for a reflux reaction. The preparation method comprises the following steps: putting the raw materials into a reaction bottle, performing a reflux reaction and filtering, and conducting evaporating under reduced pressure to remove ethanol to obtain a mixture; and adding diluted hydrochloric acid into the obtained mixture for washing, then carrying out decoloring by using activated carbon, removing the activated carbon, and evaporating ethanol under reduced pressure again to obtain tetrahydrocurcumin. According to the preparation method of tetrahydrocurcumin, dihydropyridine is adopted as a hydrogen source, reaction raw materials are non-toxic and pollution-free, the utilization rate of equipment and safety are high, the obtained product onlyneeds simple treatment, and the method is suitable for industrial production.
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Paragraph 0013-0017
(2020/11/26)
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- Use of curcumin derivative
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The invention provides the use of a curcumin derivative. The use of the curcumin derivative shown in a formula I (please see the specification for the formula), or salts of the curcumin derivative inthe preparation of drugs of anti-inflammatory diseases and/or a COX inhibitor is particularly provided. The curcumin derivative has good COX inhibitory activity and anti-inflammatory activity and canbe used for preparing the COX inhibitor and anti-inflammatory drugs. Compound 6 and compound 7 have the best effects on COX-2 inhibitory activity and anti-inflammatory activity and can be used for preparing a COX-2 inhibitor and the anti-inflammatory drugs.
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Paragraph 0039; 0054-0056; 0066
(2019/10/23)
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- A preparation method of the four mammalian keratinous tissue
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The invention provides a method for preparing tetrahydrocurcumin. The method for preparing tetrahydrocurcumin comprises the following steps: with curcumin and ethanol as raw materials and with platinum-iron-nickel hydroxide composite nano particles as a catalyst, reacting in a reaction bottle under a room temperature condition, concentrating, refrigerating, standing and crystallizing to prepare tetrahydrocurcumin. According to the method for preparing tetrahydrocurcumin, a novel catalyst is adopted to directly reduce curcumin into tetrahydrocurcumin at the room temperature, the reaction time is short, the yield, the equipment utilization rate and the safety are high, the after-treatment of an obtained product is simple, the method is suitable for industrial production, and the yield is greatly improved.
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Paragraph 0014; 0015; 0016; 0017; 0018-0023
(2017/08/24)
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- FOOD COMPOSITION FOR PREVENTING OBESITY, PHARMACEUTICAL COMPOSITION FOR TREATING OBESITY, AND ANIMAL MEDICINE FOR TREATING OBESITY, CONTAINING GINGERNONE A
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Disclosed is a composition comprising gingerenone A as an active ingredient. The composition includes a food composition for preventing obesity, a pharmaceutical composition for treating obesity and a medicine for treating animal obesity. Since the composition includes gingerenone A, which inhibits expression of the important transcriptional factors C/EBPα and PPARγ, expressed upon adipocyte differentiation, as well as FAS protein expression, the composition has superior potential for obesity prevention or treatment.
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- COMPOUNDS FOR PREVENTING, REDUCING AND/OR ALLEVIATING ITCHY SKIN CONDITION(S)
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The present invention primarily relates to the use of one or more specific compounds and/or one or more respective salt(s) thereof for preventing, reducing or alleviating itchy skin condition(s), and/or as PAR-2 antagonist. Furthermore, the present invention relates to compositions (products or, respectively, formulations), in particular for topical administration, preferably cosmetic or pharmaceutical compositions, in particular for preventing, reducing or alleviating one or more itchy skin conditions and/or for providing a PAR-2 antagonistic effect, comprising or consisting of an effect amount of such compound(s) and/or salt(s) and one or more cosmetically and/or pharmaceutically acceptable carriers.
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Paragraph 0232; 0233; 0236; 0237
(2016/02/10)
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- Synthesis of quinoline derivatives of tetrahydrocurcumin and zingerone and evaluation of their antioxidant and antibacterial attributes
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Tetrahydrocurcumin (THC, 1) and zingerone (2) are biologically active molecules originating from the important spices turmeric and ginger, respectively. Novel quinoline derivatives of THC and zingerone have been synthesised by an efficient protocol involving their reaction with substituted 2-aminobenzophenones and 2-aminoacetophenone. Radical-scavenging activities (RSA) of THC, zingerone and their quinoline derivatives were evaluated. The amino-substituted quinoline derivative of THC, 1e, showed antioxidant activity superior to those of 1 and 1a. Derivatives 1b, 1c, 1d and 1f exhibited relatively lower RSA at equimolar concentrations (~50-55 μmol). A similar trend was also seen in zingerone (2) and its derivatives (2a-2e), with 2e displaying the best RSA. Derivatives of THC (1a-1f) showed stronger antimicrobial activity than THC (1) against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Yersinia enterocolitica. Also, derivatives of zingerone (2b-2e) exhibited lower minimum inhibitory concentrations (MIC) values than zingerone (2) and its derivative, 2a for both Gram-positive and Gram-negative bacteria. The molecules may have potential pharmacological applications.
- Manjunatha,Bettadaiah,Negi,Srinivas
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p. 650 - 658
(2013/01/15)
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- Curcuminoid analogs inhibit nitric oxide production from LPS-activated microglial cells
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The chemically modified analogs, the demethy-lated analogs 4-6, the tetrahydro analogs 7-9 and the hexahydro analogs 10-12, of curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) were evaluated for their inhibitory activity on lipopolysaccharide activated nitric oxide (NO) production in HAPI microglial cells. Di-O-demethylcurcumin (5) and O- demethyldemethoxycurcumin (6) are the two most potent compounds that inhibited NO production. The analogs 5 and 6 were twofold and almost twofold more active than the parent curcuminoids 1 and 2, respectively. Moreover, the mRNA expression level of inducible NO synthase was inhibited by these two compounds. The strong neuroprotective activity of analogs 5 and 6 provide potential alternative compounds to be developed as therapeutics for neurological disorders associated with activated microglia. The Japanese Society of Pharmacognosy and Springer 2011.
- Tocharus, Jiraporn,Jamsuwan, Sataporn,Tocharus, Chainarong,Changtam, Chatchawan,Suksamrarn, Apichart
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body text
p. 400 - 405
(2012/09/10)
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- Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism
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Polyphenol curcumin, a yellow pigment, derived from the rhizomes of a plant (Curcuma longa Linn) is a natural antioxidant exhibiting a variety of pharmacological activities and therapeutic properties. It has long been used as a traditional medicine and as a preservative and coloring agent in foods. Here, curcumin-converting microorganisms were isolated from human feces, the one exhibiting the highest activity being identified as Escherichia coli. We are thus unique in discovering that E. coli was able to act on curcumin. The curcumin-converting enzyme was purified from E. coli and characterized. The native enzyme had a molecular mass of about 82 kDa and consisted of two identical subunits. The enzyme has a narrow substrate spectrum, preferentially acting on curcumin. The microbial metabolism of curcumin by the purified enzyme was found to comprise a two-step reduction, curcumin being converted NADPH-dependently into an intermediate product, dihydrocurcumin, and then the end product, tetrahydrocurcumin. We named this enzyme "NADPH-dependent curcumin/dihydrocurcumin reductase" (CurA). The gene (curA) encoding this enzyme was also identified. A homology search with the BLAST program revealed that a unique enzyme involved in curcumin metabolism belongs to the medium-chain dehydrogenase/reductase superfamily.
- Hassaninasab, Azam,Hashimoto, Yoshiteru,Tomita-Yokotani, Kaori,Kobayashi, Michihiko
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body text
p. 6615 - 6620
(2012/03/12)
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- Microbial transformation of curcumin by Rhizopus chinensis
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Curcumin (1) is a potent antioxidant and antitumor natural product. In spite of its efficacy and safety, its clinical use is hindered mainly by poor water solubility and bioavailability. Structural modification to introduce hydrophilic functions is a promising approach to resolve this problem. In the present study we first found that curcumin could be efficiently converted into glucosides by filamentous fungi including Rhizopus chinensis IFFI 03043, Absidia coerulea AS 3.3389 and Cunninghamella elegans AS 3.1207. Curcumin 4′-O-β-d-glucoside (2), together with hexahydrocurcumin (3), was isolated from a preparative-scale biotransformation with R. chinensis IFFI 03043 and characterized fully by NMR and MS. A time-course study revealed that curcumin could be efficiently converted into curcumin 4′-O-β-d- glucoside within 8 h when administered at 0.05 mmol L-1 and the productivity was 57%. Additionally, the biotransformation products of curcumin by different fungal strains were analyzed by LC/MS. At least 15 metabolites were detected, and the predominant biotransformation reaction was glucosylation. This study provides a simple, efficient and less expensive approach for the preparation of curcumin glucosides. The introduction of the glucosyl function might be able to enhance the bioavailability of curcumin.
- Zhang, Xing,Ye, Min,Li, Rui,Yin, Jun,Guo, De-An
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experimental part
p. 380 - 386
(2011/10/08)
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- Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species
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The natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the Trypanosoma and Leishmania species. The parent curcuminoids exhibited low antitrypanosomal activity (EC50 for our drug-sensitive Trypanosoma brucei brucei line (WT) of compounds 1, 2 and 3 are 2.5, 4.6 and 7.7 μM, respectively). Among 43 curcuminoid analogs and 8 pairs of 1:1 mixture of curcuminoid analogs tested, 8 pure analogs and 5 isomeric mixtures of analogs exhibited high antitrypanosomal activity in submicromolar order of magnitude. Among these highly active analogs, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (40) was the most active compound, with an EC50 value of 0.053 ± 0.007 μM; it was about 2-fold more active than the standard veterinary drug diminazene aceturate (EC50 0.12 ± 0.01 μM). Using a previously characterized diminazene-resistant T. b. brucei (TbAT1-KO) and a derived multi-drug resistant line (B48), no cross-resistance of curcuminoids was observed to the diamidine and melaminophenyl arsenical drugs that are the current treatments. Indeed, curcuminoids carrying a conjugated keto (enone) motif, including 40, were significantly more active against T. b. brucei B48. This enone motif was found to contribute to particularly high trypanocidal activity against all Trypanosoma species and strains tested. The parent curcuminoids showed low antileishmanial activity (EC50 values of compounds 1 and 2 for Leishmania mexicana amastigotes are 16 ± 3 and 37 ± 6 μM, respectively) while the control drug, pentamidine, displayed an EC50 of 16 ± 2 μM. Among the active curcuminoid analogs, four compounds exhibited EC50 values of less than 5 μM against Leishmania major promastigotes and four against L. mexicana amastigotes. No significant difference in sensitivity to curcuminoids between L. major promastigotes and L. mexicana amastigotes was observed. The parent curcuminoids and most of their analogs were also tested for their toxicity against human embryonic kidney (HEK) cells. All the curcuminoids exhibited lower toxicity to HEK cells than to T. b. brucei bloodstream forms and only one of the tested compounds showed significantly higher activity against HEK cells than curcumin (1). The selectivity index for T. b. brucei ranged from 3-fold to 1500-fold. The selectivity index for the most active analog, the enone 40, was 453-fold.
- Changtam, Chatchawan,de Koning, Harry P.,Ibrahim, Hasan,Sajid, M. Sohail,Gould, Matthew K.,Suksamrarn, Apichart
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experimental part
p. 941 - 956
(2010/04/24)
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- Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity
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Curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3), the curcuminoid constituents of the medicinal plant Curcuma longa L., have been structurally modified to 55 analogs and antimycobacterial activity against Mycobacterium tuberculosis has been evaluated. Among the highly active curcuminoids, the isoxazole analogs are the most active group, with mono-O-methylcurcumin isoxazole (53) being the most active compound (MIC 0.09 μg/mL). It was 1131-fold more active than curcumin (1), the parent compound, and was approximately 18 and 2-fold more active than the standard drugs kanamycin and isoniazid, respectively. Compound 53 also exhibited high activity against the multidrug-resistant M. tuberculosis clinical isolates, with the MICs of 0.195-3.125 μg/mL. The structural requirements for a curcuminoid analog to exhibit antimycobacterial activity are the presence of an isoxazole ring and two unsaturated bonds on the heptyl chain. The presence of a suitable para-alkoxyl group on the aromatic ring which is attached in close proximity to the nitrogen function of the isoxazole ring and a free para-hydroxyl group on another aromatic ring enhances the biological activity.
- Changtam, Chatchawan,Hongmanee, Poonpilas,Suksamrarn, Apichart
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scheme or table
p. 4446 - 4457
(2010/10/19)
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- Method and compounds for cancer treatment utilizing NFkB as a direct or ultimate target for small molecule inhibitors
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A method is described for cancer treatment through NFκB inhibition. NFκB is a direct or ultimate target for small molecule inhibitors. These small molecule inhibitors are aimed at suppression of NFκB directly or by indirect suppression of IKK, SFK kinases, or other upstream kinases. The present invention includes small molecule inhibitors comprising three, five, and seven carbon unsaturated spacers having one or two carbonyls, flanked by substituted aryl rings. The small molecule inhibitors can be symmetrical or unsymmetrical.
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Page/Page column 4; sheet 1
(2008/06/13)
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- Preparation and anti-inflammatory activities of diarylheptanoid and diarylheptylamine analogs
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Seven diarylheptylamine (12a-g) and four diarylheptanoid analogs (3-5, 9), structurally related to the natural anti-inflammatory agent oregonin (1), have been prepared from curcumin (2) for evaluation of their activity against the expression of iNOS and COX-2. Diarylheptylamine 12b and diarylheptanoid analogs can inhibit iNOS and COX-2 responses of LPS, although less potently than 1. These compounds, however, possess stronger potency than 1 against COX-2-derived PGE2 formation, of which hexahydrocurcumin (4) is the most potent one with an IC50 value of 0.7 μM.
- Lee, Su-Lin,Huang, Wei-Jan,Lin, Wan Wan,Lee, Shoei-Sheng,Chen, Chung-Hsiung
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p. 6175 - 6181
(2007/10/03)
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- Anti-oxidant activities of curcumin and related enones
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The natural product curcumin (diferuloylmethane, 1,7-bis(4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione), obtained from the spice turmeric, exhibits numerous biological activities including anti-cancer, anti-inflammatory, and anti-angiogenesis activities. Some of these biological activities may derive from its anti-oxidant properties. There are conflicting reports concerning the structural/electronic basis of the anti-oxidant activity of curcumin. Curcumin is a symmetrical diphenolic dienone. A series of enone analogues of curcumin were synthesized that included: (1) curcumin analogues that retained the 7-carbon spacer between the aryl rings; (2) curcumin analogues with a 5-carbon spacer; and (3) curcumin analogues with a 3-carbon spacer (chalcones). These series included members that retained or were devoid of phenolic groups. Anti-oxidant activities were determined by the TRAP assay and the FRAP assay. Most of the analogues with anti-oxidant activity retained the phenolic ring substituents similar to curcumin. However, a number of analogues devoid of phenolic substituents were also active; these non-phenolic analogues are capable of forming stable tertiary carbon-centered radicals.
- Weber, Waylon M.,Hunsaker, Lucy A.,Abcouwer, Steve F.,Deck, Lorraine M.,Vander Jagt, David L.
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p. 3811 - 3820
(2007/10/03)
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- Novel curcumin analogues and uses thereof
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The present invention relates to compounds capable of acting as androgen receptor antagonists, pharmaceutical formulations containing the same, and methods of use thereof. Such uses include, but are not limited to, use as antitumor agents, particularly for the treatment of cancers such as colon, skin and prostate cancer and to induce androgen receptor antagonist activity in a subject afflicted with an androgen-related affliction. Examples of androgen-related afflictions include, but are not limited to, baldness, hirsutism, behavioral disorders, acne, and uninhibited spermatogenesis wherein inhibition of spermatogenesis is so desired.
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- Synthetic derivatives of curcumin and their activity against Leishmania amazonensis
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In a previous work, the in vitro and in vivo activity of a series of diarylheptanoid derivatives against Leishmania amazonensis has been described. Based on the promising results, ten new compounds belonging to the same chemical class were synthesized and have been investigated in relation to their leishmanicidal activity. The compounds were obtained through several chemical modifications on the basic structure of curcumin (1,7-bis-(4-hydroxy-a-methoxyphenyl)-1,6-heptadiene-3,5-dione) in an attempt to increase its effectiveness and decrease the potential toxic effects. The drugs were assayed in vitro against L. amazonensis promastigotes and using pentamidine isethionate as reference drug. The results showed that the most effective compound is 1,7- bis- (4-propargyl-3-methoxyphenyl)-1, 6-heptadiene-3,5- dione, which is about ten times more efficient than the original curcumin. Nevertheless, these results did not allow us to make any correlation between the leishmanicidal activity and the chemical structure of the compounds.
- Gomes, Denise De C. F.,Alegrio, Leila Vilela,Freire de Lima, Marco Edilson,Leon, Leonor L.,Araujo, Catarina A. C.
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p. 120 - 124
(2007/10/03)
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- Antitumor agents. Part 214: Synthesis and evaluation of curcumin analogues as cytotoxic agents
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Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound 50 was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and 0.63 μg/mL, respectively.
- Ishida, Junko,Ohtsu, Hironori,Tachibana, Yoko,Nakanishi, Yuka,Bastow, Kenneth F,Nagai, Masahiro,Wang, Hui-Kang,Itokawa, Hideji,Lee, Kuo-Hsiung
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p. 3481 - 3487
(2007/10/03)
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- Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents
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A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1, 4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3(4-hydroxy-3-methoxyphenyl) acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl] 5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated β-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the β-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17α-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.
- Ohtsu, Hironori,Xiao, Zhiyan,Ishida, Junko,Nagai, Masahiro,Wang, Hui-Kang,Itokawa, Hideji,Su, Ching-Yuan,Shih, Charles,Chiang, Tzuying,Chang, Eugene,Lee, YiFen,Tsai, Meng-Yin,Chang, Chawnshang,Lee, Kuo-Hsiung
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p. 5037 - 5042
(2007/10/03)
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- Synthesis of gingerenone-A and hirsutenone
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Gingerenone-A 5, a diarylheptenone from Zingiber officinale, has been synthesized from vanillin 1 in four steps with an overall yield of 15%. Demethylation of 5 with AlCl3 gives hirsutenone 6, a metabolite of Alnus hirsute, in 36% yield. The spectral data of 5 and 6 are in agreement with those of natural metabolites 5 and 6 and both the compounds exhibited weak antibacterial activity.
- Venkateswarlu,Ramachandra,Rambabu,Subbaraju
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p. 495 - 497
(2007/10/03)
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- Involvement of the β-diketone moiety in the antioxidative mechanism of tetrahydrocurcumin
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We examined the inhibitory effects of curcumin and tetrahydrocurcumin (THC), one of the major metabolites of curcumin, on the lipid peroxidation of erythrocyte membrane ghosts induced by tert-butylhydroperoxide. The results demonstrated that THC showed a greater inhibitory effect than curcumin. To investigate the mechanism of antioxidative activity, we examined the effects of several inhibitors, such as antioxidant enzymes, hydroxyl radical scavengers, 1O2 quencher, and chelating agents for metal ions. Given that all inhibitors failed to inhibit membrane peroxidation, THC must scavenge radicals such as tert-butoxyl radical and peroxyl radical. To clarify the antioxidative mechanism of THC, in particular the role of the β-diketone moiety, dimethylated THC was incubated with peroxyl radicals generated by thermolysis of 2,2'-azobis(2,4-dimethylvaleronitrile). Four oxidation products were detected, three of which were identified as 3,4-dimethoxybenzoic acid, 3',4'-dimethoxyacetophenone, and 3-(3,4-dimethoxyphenyl)-propionic acid. The fourth oxidation product seems to be an unstable intermediate, and its detailed structure has not been determined. These results suggest that the β-diketone moiety of THC must exhibit antioxidative activity by cleavage of the C-C bond at the active methylene carbon between two carbonyls in the β-diketone moiety. Because THC is one of the major metabolites of curcumin, it may also exhibit the same physiological and pharmacological properties as the active form of curcumin in vivo by means of the β-diketone moiety as well as phenolic hydroxy groups.
- Sugiyama, Yasunori,Kawakishi, Shunro,Osawa, Toshihiko
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p. 519 - 525
(2007/10/03)
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- Antioxidative activity of tetrahydrocurcuminoids.
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In order to develop a new type of antioxidative compound which has both the phenolic and beta-diketone moiety in the same molecule, we converted three known curcuminoids, curcumin (diferuloylmethane, U1), (4-hydroxy-3-methoxycinnamoyl)methane (U2), and bis-(4-hydroxycinnamoyl)methane (U3), which are the natural antioxidants of Curcuma longa L. (tumeric), to tetrahydrocurcuminoids (THU1, THU2, and THU3, respectively) by hydrogenation, and evaluated their antioxidative activity by using linoleic acid as the substrate in an ethanol/water system. Further, we used the rabbit erythrocyte membrane ghost and rat liver microsome as in vitro systems and determined the antioxidative activity of these curcuminoids. When we evaluated their antioxidative activity by these assays, it was found that THU1 had the strongest antioxidative activity among all curcuminoids in each assay system. THU1 has been reported to be one of the main metabolites of U1 in vivo [Holder et al., Xenobiotica, 8, 761-768 (1978)]. These results suggest that THU1 must play an important role in the antioxidative mechanism of U1 in vivo by converting U1 into THU1.
- Osawa,Sugiyama,Inayoshi,Kawakishi
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p. 1609 - 1612
(2007/10/02)
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- STRUCTURES OF ANTIFUNGAL DIARYLHEPTENONES, GINGERENONES A, B, C AND ISOGINGERENONE B, ISOLATED FROM THE RHIZOMES OF ZINGIBER OFFICINALE
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Four new diarylheptenones, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (gingerenone A), 7-(3,5-dimethoxy-4-hydroxyphenyl)-1-(4-hydroxy-3-methoxyphenyl) hept-4-en-3-one (gingerenone B), 1- gingerol -> shogaol) of zingiberaceous plants.Gingerenone A exhibited a moderate anticoccidium activity in vitro and a strong antifungal effect to Pyricularia oryzae.
- Endo, Katsuya,Kanno, Emi,Oshima, Yoshiteru
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p. 797 - 799
(2007/10/02)
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