- Development of blood-brain barrier permeable nitrocatechol-based catechol O-methyltransferase inhibitors with reduced potential for hepatotoxicity
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Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.
- Silva, Tiago,Mohamed, Tarek,Shakeri, Arash,Rao, Praveen P.N.,Martínez-Gonzalez, Loreto,Pérez, Daniel I.,Martínez, Ana,Valente, Maria Jo?o,Garrido, Jorge,Uriarte, Eugenio,Serr?o, Paula,Soares-Da-silva, Patrício,Remi?o, Fernando,Borges, Fernanda
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- Synthesis and characterization of CAPE derivatives as xanthine oxidase inhibitors with radical scavenging properties
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Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.
- Choi, Wonbeen,Villegas, Valente,Istre, Hannah,Heppler, Ben,Gonzalez, Niki,Brusman, Nicole,Snider, Lindsey,Hogle, Emily,Tucker, Janelle,O?ate, Alma,O?ate, Sandra,Ma, Lili,Paula, Stefan
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- Caffeic acid phenethyl ester (CAPE): Synthesis and X-ray crystallographic analysis
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The structure of caffeic acid phenethyl ester [2-propenoic acid, 3-(3,4-dihydroxyphenyl)-, 2-phenethyl ester] (1), C17H16O4·1/2C6H 6, synthesized by base-catalyzed alkylation of caffeic acid salt with
- Son,Lobkowsky,Lewis
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Read Online
- Catechol-based inhibitors of bacterial urease
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Targeted covalent inhibitors of urease were developed on the basis of the catechol structure. Forty amide and ester derivatives of 3,4-dihydroxyphenylacetic acid, caffeic acid, ferulic acid and gallic acid were obtained and screened against Sporosarcinia pasteurii urease. The most active compound, namely propargyl ester of 3,4-dihydroxyphenylacetic acid exhibited IC50 = 518 nM andkinact/Ki = 1379 M?1 s?1. Inhibitory activity of this compound was better and toxicity lower than those obtained for the starting compound – catechol. The molecular modelling studies revealed a mode of binding consistent with structure-activity relationships.
- Pagoni, Aikaterini,Daliani, Theohari,Macegoniuk, Katarzyna,Vassiliou, Stamatia,Berlicki, ?ukasz
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supporting information
p. 1085 - 1089
(2019/03/07)
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- Caffeic acid phenethyl ester (CAPE)-derivatives act as selective inhibitors of acetylcholinesterase
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Unexpected inhibitory effects against eeAChE could be found for a newly synthesized class of caffeic acid phenethyl ester (CAPE)derivatives. Thus, phenethyl-(E)-3-(3,5-dimethoxy-4-phenethoxyphenyl)-acrylate (Ki = 1.97 ± 0.38 μM, Ki′ = 2.44 ± 0.07 μM)and 4-(2-(((E)-3-(3,4-bis(benzyloxy)phenyl)acryloyl)oxy)ethyl)-1,2-phenylene (2E,2′E)-bis(3-(3,4-bis(benzyloxy)phenyl)acrylate)(Ki = 0.72 ± 0.31 μM, Ki′ = 1.80 ± 0.21 μM)showed very good inhibition of eeAChE, while being non cytotoxic for malignant human cancer cells and non-malignant mouse fibroblasts. Also, they are weak inhibitors for BChE (from equine serum).
- Gie?el, Josephine M.,Loesche, Anne,Csuk, René
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p. 259 - 268
(2019/06/05)
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- Synthesis of Diverse Hydroxycinnamoyl Phenylethanoid Esters Using Escherichia coli
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Caffeic acid phenethyl ester (CAPE) is an ester of a hydroxycinnamic acid (phenylpropanoid) and a phenylethanoid (2-phenylethanol; 2-PE), which has long been used in traditional medicine. Here, we synthesized 54 hydroxycinnamic acid-phenylethanoid esters by feeding 64 combinations of hydroxycinnamic acids and phenylethanols to Escherichia coli harboring the rice genes OsPMT and Os4CL. The same approach was applied for ester synthesis with caffeic acid and eight different phenyl alcohols. Two hydroxycinnamoyl phenethyl esters, p-coumaroyl tyrosol and CAPE, were also synthesized from glucose using engineered E. coli by introducing genes for the synthesis of substrates. Consequently, we synthesized approximately 393.4 mg/L p-coumaroyl tyrosol and 23.8 mg/L CAPE with this approach. Overall, these findings demonstrate that the rice PMT and 4CL proteins can be used for the synthesis of diverse hydroxycinnamoyl phenylethanoid esters owing to their promiscuity and that further exploration of the biological activities of these compounds is warranted.
- Song, Min Kyung,Cho, A Ra,Sim, Geunyoung,Ahn, Joong-Hoon
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p. 2028 - 2035
(2019/02/26)
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- Antiproliferative activity and SARs of caffeic acid esters with mono-substituted phenylethanols moiety
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A series of CAPE derivatives with mono-substituted phenylethanols moiety were synthesized and evaluated by MTT assay on growth of 4 human cancer cell lines (Hela, DU-145, MCF-7 and ECA-109). The substituent effects on the antiproliferative activity were systematically investigated for the first time. It was found that electron-donating and hydrophobic substituents at 2′-position of phenylethanol moiety could significantly enhance CAPE's antiproliferative activity. 2′-Propoxyl derivative, as a novel caffeic acid ester, exhibited exquisite potency (IC50?=?0.4?±?0.02 & 0.6?±?0.03?μM against Hela and DU-145 respectively).
- Xie, Jin,Yang, Fengzhi,Zhang, Man,Lam, Celine,Qiao, Yixue,Xiao, Jia,Zhang, Dongdong,Ge, Yuxuan,Fu, Lei,Xie, Dongsheng
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p. 131 - 134
(2016/12/27)
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- Synthesis of amide and ester derivatives of cinnamic acid and its analogs: Evaluation of their free radical scavenging and monoamine oxidase and cholinesterase inhibitory activities
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A series of cinnamic acid derivatives, amides (1–12) and esters (13–22), were synthesized, and structure–activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1–10, 12–18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxy-indole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9–11, 15, 17–22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer’s disease.
- Takao, Koichi,Toda, Kazuhiro,Saito, Takayuki,Sugita, Yoshiaki
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p. 1020 - 1027
(2017/11/17)
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- Crystal form II of caffeic acid phenethyl ester, and preparation method and use thereof
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The invention provides a crystal form II of caffeic acid phenethyl ester, and a preparation method and a use thereof. The caffeic acid phenethyl ester has a structure represented by formula I, and diffraction peaks represented by 2theta diffraction angles of 6.199 DEG, 18.439 DEG, 22.560 DEG, 26.481 DEG and 30.721 DEG exist in an X-ray powder diffraction map of the crystal form II radiated with CuKalpha. The novel crystal form has a better stability than other forms. The preparation method of the novel crystal form has the characteristics of simple process, high yield and good stability.
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Paragraph 0071; 0072; 0073; 0074
(2018/02/04)
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- A rapid and practical catalytic esterification for the preparation of caffeic acid esters
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A convenient and practical catalytic method for the preparation of caffeic acid esters is reported. This esterification was carried out with high efficiency in the presence of ytterbium triflate in nitromethane without any other auxiliary reagents. The wide scope of application and especially the higher reactivity and more convenient procedure than previous methods make it a valuable application for the synthesis of caffeic acid esters and other cinnamic acid esters.
- Xie, Dongsheng,Yang, Fengzhi,Xie, Jin,Zhang, Man,Liu, Wenlu,Fu, Lei
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p. 695 - 700
(2015/02/05)
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- Synthesis and antitumor activity of feruloyl and caffeoyl derivatives This paper is dedicated to Prof. Wei-xiao Hu for his lifelong commitment to mentoring graduate students
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We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg-1.
- Chen, Hui-Zhen,Chen, You-Bao,Lv, Ya-Ping,Zeng, Fang,Zhang, Juan,Zhou, Yong-Lie,Li, Han-Bing,Chen, Li-Fei,Zhou, Bin-Jie,Gao, Jian-Rong,Xia, Chun-Nian
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p. 4367 - 4371
(2015/02/06)
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- Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel
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The TWIK-related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo.
- Rodrigues, Nuno,Bennis, Khalil,Vivier, Delphine,Pereira, Vanessa,Chatelain, Franck C.,Chapuy, Eric,Deokar, Hemantkumar,Busserolles, Jér?me,Lesage, Florian,Eschalier, Alain,Ducki, Sylvie
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p. 391 - 402
(2014/03/21)
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- Synthesis of trans-caffeate analogues and their bioactivities against HIV-1 integrase and cancer cell lines
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Forty caffeate analogues were synthesized via a convenient method starting from vanillin with moderate to good yields. The testing of biological activity of these compounds against HIV-1 integrase indicates that four compounds: bornyl caffeate, bornyl 2-nitrocaffeate, 5-nitrocaffeic acid and 5-nitrocaffeic acid phenethyl ester (5-nitroCAPE) possess a good HIV integrase inhibitory activity, IC50 19.9, 26.8, 25.0 and 13.5 μM, respectively. Twelve caffeate analogues were tested by MTT assay on growth of human hepatocellular carcinoma BEL-7404, human breast MCF-7 adenocarcinoma, human lung A549 adenocarcinoma and human gastric cancer BCG823 cell lines, respectively. And the best result is IC50 5.5 μM for CAPE against BEL-7404.
- Xia, Chun-nian,Li, Hai-bo,liu, Feng,Hu, Wei-xiao
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supporting information; experimental part
p. 6553 - 6557
(2009/09/06)
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- One-pot preparation of caffeic acid esters from 3,4-dihydroxybenzaldehyde
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A convenient one-pot process for preparing various esters of caffeic acid from 3,4-dihydroxybenzaldehyde has been developed. The alcohols or phenols react with Meldrum's acid to form malonic acid mono-esters, which, without separating, immediately react with 3,4-dihydroxybenzaldehyde to afford the desired esters in good yield. The 1H NMR data and X-ray diffraction analyses indicate that these α,β-unsaturated esters are in trans (E) form in accord with natural esters.
- Hu, Wei-Xiao,Xia, Chun-Nian,Wang, Guo-Hong,Zhou, Wei
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p. 586 - 588
(2007/10/03)
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- Synthesis of caffeic acid esters
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A new method for the preparation of caffeic acid esters was investigated. Ten caffeic acid esters were prepared by condensation of protocatechualdehyde with malonic acid mono-esters in moderate yield. Malonic acid mono-esters were prepared from the corresponding malonate di-esters. The conformations of compounds are trans (E) form.
- Xia, Chun-Nian,Hu, Wei-Xiao
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p. 332 - 334
(2007/10/03)
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- A one pot process for the preparation of caffeic acid ester derivatives
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The present invention relates to a one pot process for the preparation of caffeic acid ester derivatives of the formula I: ???whereinAr is aryl, which is unsubstituted or substituted with halogen, hydroxy, C1-6 alkyl or C1-6 alkoxy,A is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene,m is a number from 0 to 6; andB is C1-6 alkyl or aryl, which is unsubstituted or substituted with halogen, hydroxy, C1-6 alkyl or C1-6 alkoxy; ???which process comprises reacting, in a suitable solvent for esterification of a carboxylic acid derivative, a compound of the formula II: ???whereinAr and A are as defined above. ???with a halogenating reagent and alcohol of the formula III:H-(CH2)m-B ???whereinm and B are as defined above.
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- Selective antiproliferative activity of caffeic acid phenethyl ester analogues on highly liver-Metastatic murine colon 26-L5 carcinoma cell line
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Caffeic acid phenethyl ester (CAPE, 2) and its 20 analogues (1, 3-21) were prepared. These esters were tested by MTT assay on growth of murine colon 26-L5 carcinoma, murine B16-BL6 malonoma, murine Lewis lung carcinoma, human HT-1080 fibrosarcoma, human lung A549 adenocarcinoma, and human cervix HeLa adenocarcinoma cell lines. It was found that CAPE analogues possessed selective antiproliferative activity toward highly liver-metastatic murine colon 26-L5 carcinoma cell line. Among them, 4-phenylbutyl caffeate (4), (Z)-8-phenyl-7-octenyl (10a) and (E)-8-phenyl-7-octenyl (10b) caffeate showed the most potent antiproliferative activity (EC50 value, 0.02μM). In addition, CAPE (2) induced DNA fragmentation at concentrations of 1 to 10μg/mL towards murine colon 26-L5 carcinoma cells. Copyright
- Nagaoka, Takema,Banskota, Arjun H,Tezuka, Yasuhiro,Saiki, Ikuo,Kadota, Shigetoshi
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p. 3351 - 3359
(2007/10/03)
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- Chemoselective Esterification of Phenolic Acids and Alcohols
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(Matrix Presented) The Mitsunobu reaction can distinguish between alcohol and phenol hydroxyls in esterification reactions, providing an expeditious and broadly applicable entry into various phenolics and polyphenolics of biomedical and nutritional relevance.
- Appendino, Giovanni,Minassi, Alberto,Daddario, Nives,Bianchi, Federica,Tron, Gian Cesare
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p. 3839 - 3841
(2007/10/03)
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- Mechanism of toxicity of esters of caffeic and dihydrocaffeic acids
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Ten esters each of caffeic acid and dihydrocaffeic acid have recently been synthesized. Cytotoxicity evaluations of these esters versus L1210 leukemia and MCF-7 breast cancer cells in culture have led to the delineation of substantially different QSAR for each series. The L1210 QSAR for dihydrocaffeic acid esters resembles the QSAR obtained for simple phenols and estrogenic phenols. However, the QSAR pertaining to the caffeic acid esters differs considerably from its sister QSAR. This difference may be attributed to the presence of the olefinic linkage in the side chain. The octyl ester of caffeic acid is nearly ten times as toxic to the leukemia cells than the widely studied phenethyl ester, CAPE.
- Etzenhouser, Beth,Hansch, Corwin,Kapur, Sanjay,Selassie
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p. 199 - 209
(2007/10/03)
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- Method for the treatment of hyperproliferative epithelial skin diseases by topical application of hydroxylated aromatic protein cross-linking compounds
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The present invention relates to a method of treating hyperproliferative epithelial lesions by topical administration. The method prevents growth and actively cross-links these aberrant cells, thereby killing the cells. The present invention is useful in control and prevention of hyperproliferative epithelial disorders, such as HPV-infected cell lesions, actinic keratosis, melanomas, and malignant and pre-malignant carcinomas.
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- Hydroxylated aromatic inhibitors of HIV-1 integrase
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Efficient replication of HIV-1 requires integration of a DNA copy of the viral genome into a chromosome of the host cell. Integration is catalyzed by the viral integrase, and we have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE, 2), and curcumin confer inhibitory activity against HIV-1 integrase. We now extend these findings by performing a comprehensive structure-activity relationship using CAPE analogues. Approximately 30 compounds have been prepared as HIV integrase inhibitors based on the structural lead provided by CAPE, which has previously been shown to exhibit an IC50 value of 7 μM in our integration assay. These analogues were designed to examine specific features of the parent CAPE structure which may be important for activity. Among the features examined for their effects on inhibitory potency were ring substitution, side chain length and composition, and phenyl ring conformational orientation. In an assay which measured the combined effect of two sequential steps, dinucleotide cleavage and strand transfer, several analogues have IC50 values for 3'-processing and strand transfer lower than those of CAPE. Inhibition of strand transfer was assayed using both blunt-ended and 'precleaved' DNA substrates. Disintegration using an integrase mutant lacking the N-terminal zinc finger and C-terminal DNA-binding domains was also inhibited by these analogues, suggesting that the binding site for these compounds resides in the central catalytic core. Several CAPE analogues were also tested for selective activity against transformed cells. Taken together, these results suggest that the development of novel antiviral agents for the treatment of acquired immune deficiency syndrome can be based upon inhibition of HIV-1 integrase.
- Burke Jr.,Fesen,Mazumder,Wang,Carothers,Grunberger,Driscoll,Kohn,Pommier
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p. 4171 - 4178
(2007/10/03)
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- Lipophilic Derivatives of Caffeic Acid as Lipoxygenase Inhibitors with Antioxidant Properties
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Caffeic acid phenethyl ester is an active component of propolis.We obtained two derivatives of caffeic acid, phenethyl ester and N,N'-dicyclohexyl-O-(3,4-dihydrocinnamoyl)isourea.Both compounds inhibit barley 5-lipoxygenase and soybean 15-lipoxygenase at a micromolar range of concentrations.The inhibition is uncompetitive, dose-dependent, and reversible, as shown by experiments with barley 5-lipoxygenase.The derivatives also exhibit antioxidant properties and at concentrations 5 and 10 μM, respectively, completely block formation of the reactive oxygen species inhuman neutrophils and in cell-free xanthine-xanthine oxydase system.Key words: caffeic acid, lipophilic derivatives, lipoxygenase, enzyme inhibition, respiratory burst, xanthine oxidase.
- Mirzoeva, O.K.,Sud'ina, G.F.,Pushkareva, M.A.,Korshunova, G.A.,Sumbatyan, N.V.,Varfolomeev, S.D.
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p. 124 - 131
(2007/10/02)
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