- Synergistic antifungal effects of curcumin derivatives as fungal biofilm inhibitors with fluconazole
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Lack of novel antifungal agents and severe drug resistance has led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with anti-resistant potency are highly desirable. Thus, derivati
- Dong, Huai-Huai,Wang, Yuan-Hua,Peng, Xue-Mi,Zhou, He-Yang,Zhao, Fei,Jiang, Yuan-Ying,Zhang, Da-Zhi,Jin, Yong-Sheng
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p. 1079 - 1088
(2021/02/11)
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- Influence of side-chain changes on histone deacetylase inhibitory and cytotoxicity activities of curcuminoid derivatives
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Using curcuminoids as lead compounds, fifty-nine curcuminoid derivatives with different side chains at the phenolic moiety were synthesized. All compounds were investigated for their histone deacetylase (HDAC) inhibitory activities. The potent pan-HDAC in
- Kumboonma, Pakit,Phaosiri, Chanokbhorn,Saenglee, Somprasong,Samankul, Arunta,Senawong, Gulsiri,Senawong, Thanaset,Somsakeesit, La-or,Yenjai, Chavi
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supporting information
(2020/04/10)
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- A new family of homoleptic copper complexes of curcuminoids: Synthesis, characterization and biological properties
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We report herein the synthesis and crystal structures of five new homoleptic copper complexes of curcuminoids. The scarcity of reports of homoleptic complex structures of curcuminoids is attributed to the lack of crystallinity of such derivatives, and therefore, their characterization by single crystal X-ray diffraction is rare. The ligand design suppressing the phenolic interaction by esterification or etherification has afforded a significant increase in the number of known crystal structures of homoleptic metal complexes of curcuminoids revealing more favorable crystallinity. The crystal structures of the present new copper complexes show four-fold coordination with a square planar geometry. Two polymorphs were found for DiBncOC-Cu when crystallized from DMF. The characterization of these new complexes was carried out using infrared radiation (IR), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and single crystal X-ray diffraction (SCXRD) and the antioxidant and cytotoxic activity of the obtained complexes was evaluated.
- Meza-Morales, William,Machado-Rodriguez, Juan C.,Alvarez-Ricardo, Yair,Obregón-Mendoza, Marco A.,Nieto-Camacho, Antonio,Toscano, Rubén A.,Soriano-García, Manuel,Cassani, Julia,Enríquez, Raúl G.
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- A Flexible Strategy for Modular Synthesis of Curcuminoid-BF2/Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines
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A facile protocol that enables synthetic interconversion of CUR-BF2 and CUR compounds is described that significantly widens the preparative scope of curcuminoids, providing access to larger libraries of compounds, thus enabling comparative antiproliferative and apoptotic study of a larger library of synthetic analogs in cancer cell lines.
- Abonia, Rodrigo,Bunge, Scott D.,Laali, Kenneth K.,Raja Somu, Dawn,Wang, Esther C.
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- Design, synthesis and evaluation of curcumin-based fluorescent probes to detect Aβ fibrils
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Amyloid β fibrillation is an early event in Alzheimer's disease, so its detection is important to understand its roles in Alzheimer's disease. Curcumin, which has poor water solubility, has been reported to have many pharmacological activities including potent anti-amyloid β fibril activity in Alzheimer's disease. In this study, we found that curcumin analogues with the fluorescence property instead of non-inhibition of amyloid β fibrils. The development of new curcumin analogue, Me-CUR (9), as fluorescent switchable probe to detect amyloid β fibrils is described. Me-CUR (9) shows excellent fluorescence, especially higher than ThT (4), in the presence of amyloid β fibrils. These results suggest that Me-CUR (9) can become a useful in vitro amyloid fluorescence sensor for diagnosis of Alzheimer's disease.
- Sato, Taki,Hotsumi, Mayumi,Makabe, Koki,Konno, Hiroyuki
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supporting information
p. 3520 - 3525
(2018/10/15)
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- NOVEL CURCUMINOID-INSPIRED SYNTHETIC COMPOUNDS AS ANTI-TUMOR AGENTS
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Novel CUR- and CUR-BF2 compounds exhibiting anti-tumor properties are presented. CUR compounds bearing fluorinated moieties with selective fluorine introduction into the α-carbonyl moiety as well as CUR-BF2 adducts and CURs with dive
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Paragraph 0225; 0233
(2019/01/04)
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- CURCUMIN DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a new curcumin derivative. SOLUTION: A chemical compound is shown by formula (1) as follows. In the formula, R1 is a 1-5C alkyl group, a 2-5C alkenyl group or a 2-5C alkynyl group; R2 is a 1-5C alkyl group, a 2-5C alkenyl group or a 2-5C alkynyl group; n1 is an integral number of 1-4, and when n1 is 2 or more, R1 may be the same or different from each other; and n2 is an integral number of 1-4, and when n2 is 2 or more, R2 may be the same or different from each other. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0039; 0046; 0047; 0048
(2018/10/19)
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- Design, synthesis, and evaluation of curcumin analogues as potential inhibitors of bacterial sialidase
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Sialidases are key virulence factors that remove sialic acid from the host cell surface glycan, unmasking receptors that facilitate bacterial adherence and colonisation. In this study, we developed potential agents for treating bacterial infections caused by Streptococcus pneumoniae Nan A that inhibit bacterial sialidase using Turmeric and curcumin analogues. Design, synthesis, and structure analysis relationship (SAR) studies have been also described. Evaluation of the synthesised derivatives demonstrated that compound 5e was the most potent inhibitor of S. pneumoniae sialidase (IC50 = 0.2 ± 0.1 μM). This compound exhibited a 3.0-fold improvement in inhibitory activity over that of curcumin and displayed competitive inhibition. These results warrant further studies confirming the antipneumococcal activity 5e and indicated that curcumin derivatives could be potentially used to treat sepsis by bacterial infections.
- Kim, Bo Ram,Park, Ji-Young,Jeong, Hyung Jae,Kwon, Hyung-Jun,Park, Su-Jin,Lee, In-Chul,Ryu, Young Bae,Lee, Woo Song
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p. 1256 - 1265
(2018/08/28)
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- Activation of anti-oxidant Nrf2 signaling by enone analogues of curcumin
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Inflammation and oxidative stress are common in many chronic diseases. Targeting signaling pathways that contribute to these conditions may have therapeutic potential. The transcription factor Nrf2 is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. Nrf2 is widespread in the CNS and is recognized as an important regulator of brain inflammation. The natural product curcumin exhibits numerous biological activities including ability to induce the expression of Nrf2-dependent phase II and anti-oxidant enzymes. Curcumin has been examined in a number of clinical studies with limited success, mainly owing to limited bioavailability and rapid metabolism. Enone analogues of curcumin were examined with an Nrf2 reporter assay to identify Nrf2 activators. Analogues were separated into groups with a 7-carbon dienone spacer, as found in curcumin; a 5-carbon enone spacer with and without a ring; and a 3-carbon enone spacer. Activators of Nrf2 were found in all three groups, many of which were more active than curcumin. Dose-response studies demonstrated that a range of substituents on the aromatic rings of these enones influenced not only the sensitivity to activation, reflected in EC50 values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2 by these analogues.
- Deck, Lorraine M.,Hunsaker, Lucy A.,Vander Jagt, Thomas A.,Whalen, Lisa J.,Royer, Robert E.,Vander Jagt, David L.
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supporting information
p. 854 - 865
(2017/12/13)
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- Synthesis of curcuminoids and evaluation of their cytotoxic and antioxidant properties
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Curcumin (1) and ten derivatives (2-11) were synthesized and evaluated as cytotoxic and antioxidant agents. The results of primary screening by Sulforhodamine B assay against five human cancer cell lines (U-251 MG, glioblastoma; PC-3, human prostatic; HCT-15, human colorectal; K562, human chronic myelogenous leukemia; and SKLU-1, non-small cell lung cancer) allowed us to calculate the half maximal inhibitory concentration (IC50) values for the more active compounds against HCT-15 and K562 cell lines. Compounds 2 and 10 were the most active against both cell lines and were more active than curcumin itself. Thiobarbituric acid reactive substances (TBARS) assay showed that 7 has potent activity; even stronger than curcumin, α-tocopherol, and quercetin.
- Lozada-García, María Concepción,Enríquez, Raúl G.,Ramírez-Apán, Teresa O.,Nieto-Camacho, Antonio,Palacios-Espinosa, Juan Francisco,Custodio-Galván, Zeltzin,Soria-Arteche, Olivia,Pérez-Villanueva, Jaime
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- Design, synthesis, and evaluation of curcumin derivatives as Nrf2 activators and cytoprotectors against oxidative death
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Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent Nrf2 activator and cancer chemopreventive agent. In this study, we synthesized a series of curcumin analogs by introducing the geminal dimethyl substituents on the active methylene group to find more potent Nrf2 activators and cytoprotectors against oxidative death. The geminally dimethylated and catechol-type curcumin analog (compound 3) was identified as a promising lead molecule in terms of its increased stability and cytoprotective activity against the tert-butyl hydroperoxide (t-BHP)-induced death of HepG2 cells. Mechanism studies indicate that its cytoprotective effects are mediated by activating the Nrf2 signaling pathway in the Michael acceptor- and catechol-dependent manners. Additionally, we verified by using copper and iron ion chelators that the two metal ion-mediated oxidations of compound 3 to its corresponding electrophilic o-quinone, contribute significantly to its Nrf2-dependent cytoprotection. This work provides an example of successfully designing natural curcumin-directed Nrf2 activators by a stability-increasing and proelectrophilic strategy.
- Tu, Zhi-Shan,Wang, Qi,Sun, Dan-Dan,Dai, Fang,Zhou, Bo
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- Synthesis, characterization and anticancer activity of a series of curcuminoids and their half-sandwich ruthenium(II) complexes
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A series of curcuminoids (L1–L7) and their corresponding (η6-p-cymene)RuII(Cur)Cl complexes (1–7) were synthesized and characterized using 1H NMR spectroscopy, elemental analysis and high-resolution e
- Li, Peiyuan,Su, Wei,Lei, Xiaolin,Xiao, Qi,Huang, Shan
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- The in vitro antitumor activity of arene-ruthenium(II) curcuminoid complexes improves when decreasing curcumin polarity
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The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI?=?(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII?=?(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC50 (μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC50 are halved. Therefore, after replacing OH curcumin groups with OCH3, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity.
- Caruso, Francesco,Pettinari, Riccardo,Rossi, Miriam,Monti, Elena,Gariboldi, Marzia Bruna,Marchetti, Fabio,Pettinari, Claudio,Caruso, Alessio,Ramani, Modukuri V.,Subbaraju, Gottumukkala V.
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- Reductive ring opening of 3,5-bis(2-arylethenyl)isoxazoles with molybdenum hexacarbonyl: A novel route to symmetrical and unsymmetrical curcumin derivatives
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Curcumin derivatives were successfully synthesized from 3,5-dimethylisoxazole by lateral metalation and condensation with various aromatic aldehydes sequentially at C5- and C3-methyl groups. After dehydration, further transformation of isoxazole ring to β-diketone moiety was accomplished by reductive ring opening using molybdenum hexacarbonyl [Mo(CO)6] and subsequent simple acidic hydrolysis.
- Hahnvajanawong, Viwat,Thaima, Thanaphat,Tearavarich, Ruchanok,Theramongkol, Parinya
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p. 127 - 135
(2016/05/09)
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- Kinetics of curcumin oxidation by 2,2-diphenyl-1-picrylhydrazyl (DPPH): An interesting case of separated coupled proton-electron transfer
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The decay of dpph in absolute ethanol at 25 °C and in the presence of curcumin (1), 4-methylcurcumin (3), 4,4-dimethylcurcumin (4) or curcumin 4′-methyl ether (5) follows bi-exponential kinetics. These unusual reaction kinetics are compatible with a two-step process in which an intermediate accumulates in a reversible first step followed by an irreversible process. As in other similar cases (Foti et al., Org. Lett., 2011, 13, 4826-4829), we have hypothesised that the intermediate is a π-stacked complex, formed between one curcumin anion (in the case of 1, 3 and 5 the enolate anion) and the picryl moiety of dpph, in which an intra-complex electron transfer from the (enolate) anion takes place. By comparing the kinetics of curcumin 4′,4′′-dimethyl ether (2) (no phenolic OH), (5) (one phenolic OH) and (1) (two phenolic OHs), we have deduced that the electron transfer process must be accompanied by a simultaneous proton transfer from the phenolic OHs to the bulk solvent (separated coupled proton-electron transfer). The rate constants kα for the forward reaction of 2, 5 and 1 with dpph are in fact ~0, 7.5 × 103 and 1.8 × 104 M-1 s-1, respectively, in a clear dependence on the number of phenolic OHs.
- Foti, Mario C.,Slavova-Kazakova, Adriana,Rocco, Concetta,Kancheva, Vessela D.
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supporting information
p. 8331 - 8337
(2016/09/09)
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- Fluoro-curcuminoids and curcuminoid-BF2adducts: Synthesis, X-ray structures, bioassay, and computational/docking study
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A series of α-carbonyl fluorinated curcuminoids were synthesized by direct mono- and difluorination with Selectfluor (F-TEDA-BF4) at r.t. without using a base or additive. Ring fluorinated/trifluoromethylated curcuminoid-BF2adducts were synthesized by reaction of the corresponding benzaldehydes with acetylacetone-BF2. Decomplexation of CUR-BF2adducts under microwave irradiation gave the corresponding curcuminoids. Multinuclear NMR and X-ray analysis confirm that curcuminoids bearing fluorines or trifluoromethyl groups in the aryl rings as well as those that are monofluorinated at the active methylene position all exist as enol tautomers. The α,α-difluorination brings about significant conformational change as these curcuminoids become fixed in the 1,3-diketone configuration. The X-ray structures of CUR-BF2complexes are consistent with the formation of symmetrical adducts with equal B[sbnd]O bond distances. The anti-proliferative activity of these compounds were tested by in-vitro bioassay against several different cancer cell lines. The corresponding CUR-BF2adducts exhibited exceptionally high activities at micromolar and in some cases nanomolar concentrations that greatly surpass the activity of parent curcumin. Computational docking calculations were performed to gauge binding energies of these compounds in HER2 protein, and in 20S proteasome, for comparison with the bioassay-derived activity data.
- Laali, Kenneth K.,Rathman, Benjamin M.,Bunge, Scott D.,Qi, Xin,Borosky, Gabriela L.
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- A Fluorescent Chemosensor for Al3+Based on C O Isomerization Derivated from Curcumin
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A simple and nontoxic fluorescent chemosensor of di-O-methyl curcumin has been prepared from curcumin. The sensor exhibited selective and sensitive fluorescent responses toward Al3+over a wide range of metal ions, such as Mn2+, Ce3+, Pt2+, Sn4+, Hg+, Sb3+, K+, Ca2+, Mg2+, Ba2+, Cu2+, Ni2+, Na+, NH4+, Ag+, Pb2+, Zn2+, Fe2+, Fe3+, Hg2+and Cr3+in ethanol/water. The free ligand showed quite weak fluorescence emission due to the isomerization of C O double bond in the excited state, however, after addition of Al3+, fluorescence emission results in a prominent fluorescence enhancement.
- Li, Zhengyi,Yan, Jinbei,Yin, Yue,Zhang, Zhihui,Wang, Zhiming,Xu, Defeng,Sun, Xiaoqiang
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p. 657 - 661
(2016/07/22)
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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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- Iodine impregnated nano neutral alumina as an efficient catalyst for one pot green synthesis of curcumin analogues by microwave irradiation
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Sixteen substituted curcumin analogs are synthesized in one pot by iodine impregnated nano neutral alumina catalyst under microwave irradiation. This catalyst shows higher reactivity by which it offered the reaction with higher yields and less reaction time. The prepared catalyst was characterized by FE-SEM, EDX and BET isotherm surface area. Also, the synthesized products were characterized by FT-IR, 1H NMR, 13C NMR, mass and elemental analysis.
- Elavarasan,Bhakiaraj,Chellakili,Elavarasan,Gopalakrishnan
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p. 237 - 243
(2014/05/20)
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- Synthesis and characterization of new curcumin derivatives as potential chemotherapeutic and antioxidant agents
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Preclinical Research The purpose of this work was to synthesize a series of symmetrical analogs (CA2-CA7) of curcumin and determine their efficacy as antioxidant and anticancer agents in vitro. The six analogs were successfully synthesized and characterized, one of which, CA6, had not been previously reported in the literature. With the exception of CA2, the analogs had lower predicted aqueous solubilities and higher partition coefficients than curcumin. Two analogs, CA2 and CA3, had lower potencies as anticancer agents compared with curcumin, while CA6 had a slightly higher IC50 value. Two different trends in the antioxidant capabilities of curcumin and its analogs were determined when assessed in vitro or in cell culture. The in vitro DPPH assay clearly showed curcumin as the strongest antioxidant as compared with the analogs when tested at the same concentration or at their IC50 value. The cell culture-based reactive oxygen species/reactive nitrogen species assay indicated that CA3 and CA6 were equal to curcumin in their free radical scavenging ability at the same concentration, but when curcumin and its analogs were tested at their respective IC50 values, CA4 and CA5 showed excellent antioxidant capacities. These results indicate that in cell culture, the ability of these analogs to produce antioxidant effects may be tied to their downstream effects.
- Ciochina, Roxana,Savella, Chasity,Cote, Brianna,Chang, Davis,Rao, Deepa
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- Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor
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Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed.
- Endo, Hitoshi,Nikaido, Yuri,Nakadate, Mamiko,Ise, Satomi,Konno, Hiroyuki
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p. 5621 - 5626
(2015/01/08)
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- Functionalized curcumin analogs as potent modulators of the Wnt/β-catenin signaling pathway
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Osteosarcoma is a primary bone malignancy with aggressive metastatic potential and poor prognosis rates. In our earlier work we have investigated the therapeutic potential of curcumin as an anti-invasive agent in osteosarcoma by its ability to regulate the Wnt/β-catenin signaling pathway. However, the clinical use of curcumin is limited owing to its low potency and poor pharmacokinetic profile. In this study, an attempt was made to achieve more potent Wnt inhibitory activity in osteosarcoma cells by carrying out synthetic chemical modifications of curcumin. We synthesized a total of five series consisting of 43 curcumin analogs and screened in HEK293T cells for inhibition of β-catenin transcriptional activity. Six promising analogs, which were 6.5- to 60-fold more potent than curcumin in inhibiting Wnt activity, were further assessed for their anti-invasive activity and Wnt inhibitory mechanisms. Western blot analysis showed disruption of β-catenin protein nuclear translocation following treatment with analogs 2f, 3c and 4f. Using transwell assays, we also found that these compounds were more potent than 1a (curcumin) in impeding the invasion of osteosarcoma cells, possibly through suppressing MMP-9 activity. Structure-activity-relationship studies revealed that Wnt inhibitory effects could be enhanced by shortening and restraining the flexibility of the 7-carbon linker moiety connecting the terminal aromatic rings of curcumin and substituting both rings with appropriate substituents. Our results demonstrate that the synthesized curcumin analogs are more potent Wnt inhibitors in osteosarcoma cell lines as compared to parental curcumin and are good lead compounds for further development. Future in vivo tests with these compounds will define their therapeutic potentials as promising drug candidates for clinical treatment of osteosarcoma.
- Leow, Pay-Chin,Bahety, Priti,Boon, Choon Pei,Lee, Chong Yew,Tan, Kheng Lin,Yang, Tianming,Ee, Pui-Lai Rachel
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- One pot synthesis, structural and spectral analysis of some symmetrical curcumin analogues catalyzed by calcium oxide under microwave irradiation
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A series of sixteen number of curcumin analogues have been synthesized under microwave irradiation using calcium oxide as a catalyst. The synthesized compounds have been characterized using FT-IR, MS, elemental analysis, 1H and 13C N
- Elavarasan, S.,Bhakiaraj, D.,Chellakili, B.,Elavarasan, T.,Gopalakrishnan, M.
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p. 717 - 721,5
(2012/12/11)
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- Significant enhancement in radical-scavenging activity of curcuminoids conferred by acetoxy substituent at the central methylene carbon
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For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. Curcumin has a unique structure with phenolic hydroxyl g
- Kim, Mi Kyoung,Jeong, Wooseong,Kang, Jihoon,Chong, Youhoon
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experimental part
p. 3793 - 3800
(2011/08/06)
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- Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-κB signaling pathway
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A series of curcumin analogues including new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogues can effectively decrease the growth of a panel of lung cancer cells at submicromolar and low micromolar concentrations. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogues exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogues also reduced the tumorigenic potential of cancer cells in a clonogenic assay.
- Qiu, Xu,Du, Yuhong,Lou, Bin,Zuo, Yinglin,Shao, Weiyan,Huo, Yingpeng,Huang, Jianing,Yu, Yanjun,Zhou, Binhua,Du, Jun,Fu, Haian,Bu, Xianzhang
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scheme or table
p. 8260 - 8273
(2011/02/21)
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- Structure-activity relationship studies of curcumin analogues
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Two series of curcumin analogues, a total of twenty-four compounds, were synthesized and evaluated. The most potent compound, compound 23, showed potent growth inhibitory activities on both prostate and breast cancer lines with IC50 values in sub-micromolar range, fifty times more potent than curcumin. Curcumin analogues might be potential anti-tumor agents for breast and prostate cancers.
- Fuchs, James R.,Pandit, Bulbul,Bhasin, Deepak,Etter, Jonathan P.,Regan, Nicholas,Abdelhamid, Dalia,Li, Chenglong,Lin, Jiayuh,Li, Pui-Kai
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scheme or table
p. 2065 - 2069
(2009/11/30)
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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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- 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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- Antitumor agents 247. New 4-ethoxycarbonylethyl curcumin analogs as potential antiandrogenic agents
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4-Ethoxycarbonylethyl curcumin (ECECur) (3) is a current drug candidate for the treatment of prostate cancer. Due to problems inherent in the tautomerism of ECECur, 4-fluoro-4-ethoxycarbonylethyl curcumin (4) and 4- ethoxycarbonylethylenyl curcumin (5) were designed and synthesized. These two target compounds and their synthetic intermediates (4-9) were evaluated for their inhibitory activity against androgen receptor transcription in LNCaP and PC-3 prostate cancer cell lines. While the enol-keto analogs showed varying anti-androgen potencies, the di-keto analogs showed no activity. Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-AR activity of 4-ethoxycarbonylethylenyl curcumin, but a negative impact on the activity of ECECur. With potent anti-AR activity, di-tetrapyranylated 4-ethoxycarbonylethylenyl curcumin (9), which exists in only one form, is a good drug lead for further structural modification. Based on the SAR information obtained from the above study, five new compounds were designed and subsequently synthesized. Among them, compound 10 was found to be the most potent anti-AR agent and is considered to be a promising drug candidate for the treatment of prostate cancer.
- Lin, Li,Shi, Qian,Su, Ching-Yuan,Shih, Charles C.-Y.,Lee, Kuo-Hsiung
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p. 2527 - 2534
(2007/10/03)
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- Anti-allergic principles from Thai zedoary: Structural requirements of curcuminoids for inhibition of degranulation and effect on the release of TNF-α and IL-4 in RBL-2H3 cells
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The 80% aqueous acetone extract of the rhizomes of Curcuma zedoaria cultivated in Thailand (Thai zedoary) was found to inhibit release of β-hexosaminidase, as a marker of antigen-IgE-mediated degranulation, in RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice. Effects of four curcuminoids from Thai zedoary and several related compounds on the degranulation were examined. Among them, curcumin showed the highest activity against β-hexosaminidase release with IC50 of 5.3 μM, followed by bisdemethoxycurcumin (IC50 = 11 μM). With regard to the structural requirements of curcuminoids for the activity, the conjugated olefins at the 1-7 positions and the 4′- or 4″-hydroxyl groups of curcuminoids were suggested to be essential for the strong activity, whereas the 3′- or 3″-methoxyl group only enhanced the activity. Furthermore, effects of curcumin and bisdemethoxycurcumin on calcium ionophores (A23187 and ionomycin)-induced degranulation and antigen-induced release of TNF-α and IL-4 were examined. The 80% aqueous acetone extract of the rhizomes of Curcuma zedoaria cultivated in Thailand (Thai zedoary) was found to inhibit release of β-hexosaminidase, as a marker of antigen-IgE-mediated degranulation, in RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice. From the active fraction, four curcuminoids (curcumin, dihydrocurcumin, tetrahydrodemethoxycurcumin, and tetrahydrobisdemethoxycurcumin) were isolated together with two bisabolane-type sesquiterpenes, and the effects of four curcuminoids from Thai zedoary and several related compounds on the degranulation were examined. Among them, curcumin showed the highest activity against β-hexosaminidase release with IC50 of 5.3 μM, followed by bisdemethoxycurcumin (IC50 = 11 μM). With regard to the structural requirements of curcuminoids for the activity, the conjugated olefins at the 1-7 positions and the 4′- or 4″-hydroxyl groups of curcuminoids were suggested to be essential for the strong activity, whereas the 3′- or 3″-methoxyl group only enhanced the activity. Furthermore, effects of curcumin and bisdemethoxycurcumin on calcium ionophores (A23187 and ionomycin)-induced degranulation and antigen-induced release of TNF-α and IL-4 were examined.
- Matsuda, Hisashi,Tewtrakul, Supinya,Morikawa, Toshio,Nakamura, Akihiko,Yoshikawa, Masayuki
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p. 5891 - 5898
(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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- 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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- 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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