- NOVEL COMPOUNDS USEFUL AS NEAR-INFRARED FLUORESCENT PROBES SELECTIVELY BINDING TO TAU AGGREGATES AND METHOD OF PREPARING THE SAME
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Disclosed are a compound with near-infrared fluorescence that selectively binds to tau aggregates, a method for preparing the same, a tau-targeting near-infrared fluorescent probe including the compound, a composition for detecting a tau fiber protein containing the near-infrared fluorescent probe as an active ingredient, and the use of the composition for the diagnosis of tauopathy. In particular, the compound does not bind to an amyloid beta protein and has high selectivity to a tau aggregate, specifically reported as an etiology of the initial state of tauopathy, thus being useful as a near-infrared fluorescent detector for detecting a tau fiber protein for early diagnosis of a tauopathy including Alzheimer's disease.
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Paragraph 0184-0187; 0192
(2021/08/20)
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- Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics
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Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
- Buijs, Ned,Campagna, Roberto,Emanuelli, Monica,Gao, Yongzhi,Innocenti, Paolo,Jespers, Willem,Martin, Nathaniel I.,Parsons, Richard B.,Sartini, Davide,Van Haren, Matthijs J.,Van Westen, Gerard J. P.,Zhang, Yurui,Gutiérrez-De-Terán, Hugo
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p. 12938 - 12963
(2021/09/11)
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- Synthesis of Nitrogen-Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells
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Two series of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin chloroacrylamide 13 e displayed the lowest IC50 values for both MCF-7 (0.5 μm) and PC3 (0.3 μm) cells, about 26-fold more potent than goniothalamin (1). Besides its higher potency, compound 13 e also displayed much higher selectivity than goniothalamin. In contrast, goniothalamin isobutyramide 13 c was the most potent analogue against Caco-2 cells (IC50=0.8 μm), about 10-fold more potent and 17-fold more selective than 1. These results reveal the potential of compounds 13 c and 13 e for further in vivo studies, representing the first goniothalamin analogues with IC50 values in the low micromolar range and high selectivity against MCF-7, Caco-2, and PC3 cancer cell lines.
- Meirelles, Matheus A.,Braga, Carolyne B.,Ornelas, Catia,Pilli, Ronaldo A.
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supporting information
p. 1403 - 1417
(2019/08/01)
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- Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant Staphylococcus aureus
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Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound 4a. Derivative 47 displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, 47 displayed excellent efficacy against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo.
- Ni, Shuaishuai,Li, Baoli,Chen, Feifei,Wei, Hanwen,Mao, Fei,Liu, Yifu,Xu, Yixiang,Qiu, Xiaoxi,Li, Xiaokang,Liu, Wenwen,Hu, Linghao,Ling, Dazheng,Wang, Manjiong,Zheng, Xinyu,Zhu, Jin,Lan, Lefu,Li, Jian
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supporting information
p. 233 - 237
(2018/03/21)
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- Gold catalyzed Heck-coupling of arenediazonium o-benzenedisulfonimides
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Diazonium salts, and precisely arenediazonium o-benzenedisulfonimides, have been used for the first time as efficient electrophilic partners in gold catalyzed Heck-coupling reactions. The synthetic protocol was general, easy and gave the target products in satisfactory yields. Mechanistic insights revealed the fundamental roles of the o-benzenedisulfonimide anion as an electron transfer agent thath promotes a radical pathway that does not require the presence of photocatalysts or external oxidants.
- Barbero, Margherita,Dughera, Stefano
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p. 295 - 301
(2018/01/12)
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- Anti-tumor compounds
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The invention discloses anti-tumor compounds. The compounds target a Neddylation pathway. The compounds have a structural formula represented in a general formula I or a general formula II or a general formula III or a general formula IV or a general formula V or a general formula VI. The compounds have good anti-tumor activity, and multiple compounds are close to a positive control drug MLN4924,and can be used as good anti-tumor compounds. A combined therapy is provided through combined adoption of the compounds and compositions with other drugs, and a part of the same compositions can be formed by the drugs, or the drugs can be administered as separate components at the same time or at different time.
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Paragraph 0024; 0025; 0026; 0027; 0028; 0029
(2019/01/08)
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- Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo
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Our previous work (Wang et al. J. Med. Chem. 2016, 59, 4831-4848) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.
- Ni, Shuaishuai,Wei, Hanwen,Li, Baoli,Chen, Feifei,Liu, Yifu,Chen, Wenhua,Xu, Yixiang,Qiu, Xiaoxia,Li, Xiaokang,Lu, Yanli,Liu, Wenwen,Hu, Linhao,Lin, Dazheng,Wang, Manjiong,Zheng, Xinyu,Mao, Fei,Zhu, Jin,Lan, Lefu,Li, Jian
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supporting information
p. 8145 - 8159
(2017/10/18)
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- Asymmetric Organocatalytic Stepwise [2+2] Entry to Tetra-Substituted Heterodimeric and Homochiral Cyclobutanes
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An asymmetric synthesis of tetra-substituted cyclobutanes involving an organocatalytic, stepwise [2+2]-cycloaddition is described. The secondary-amine-catalyzed method allows for the hetero-dimerization of two different cinnamic-acid-derived sub-units, opening a novel one-step assembly to densely functionalized, head-to-tail coupled dimeric cyclobutanes in high enantiomeric excess. A series of selective synthetic interconversions in these sensitive cycloadducts is also described.
- Nielsen, Alex J.,Jenkins, Hilary A.,McNulty, James
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supporting information
p. 9111 - 9115
(2016/07/14)
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- Stereoselective organocatalytic oxidation of alcohols to enals: A homologation method to prepare polyenes
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A novel method for organocatalytic oxidation through oxidative enamine catalysis was developed with excellent compatibility for the direct syntheses of enals from simple saturated alcohols. By using this amine-catalyzed IBX-oxidation, a wide range of aromatic and aliphatic substituted enals were successfully generated in high yields and exclusively stereoselective E-geometry. Moreover, varying the solvents and/or the loading amounts of IBX allowed for the selective oxidation of alcohols and aldehydes. Importantly, the homologous application of this method provided a selective and efficient way of preparing various highly sensitive conjugated polyene frameworks, which are enriched in natural products.
- Chen, Xiaobei,Zhang, Yinan,Wan, Huixin,Wang, Wei,Zhang, Shilei
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p. 3532 - 3535
(2016/03/04)
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- Efficient preparation of trans-α,β-unsaturated aldehydes from saturated aldehydes by oxidative enamine catalysis
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A mild and highly efficient amine-catalyzed, IBX-mediated oxidation of aldehydes to (E) selective α,β-unsaturated aldehydes has been achieved in good yields. The process features a new oxidation of enamines to iminium ions in a catalytic fashion.
- Zhang, Shilei,Xie, Hexin,Song, Aiguo,Wu, Deyan,Zhu, Jin,Zhao, Sihan,Li, Jian,Yu, Xinhong,Wang, Wei
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experimental part
p. 1932 - 1936
(2012/03/09)
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- An efficient palladium-catalyzed synthesis of cinnamaldehydes from acrolein diethyl acetal and aryl iodides and bromides
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(Matrix presented) The reaction of aryl iodides and bromides with acrolein diethyl acetal in the presence of Pd(OAc)2, nBu 4NOAc, K2CO3, KCl, and DMF, at 90°C until the disappearance of the acetal followed by the addition of 2 N HCl to the crude reaction mixture, affords cinnamaldehydes in good to high yields. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, dialkylamino, nitrile, and nitro groups. The presence of substituents close to the oxidative addition site does not hamper the reaction.
- Battistuzzi, Gianfranco,Cacchi, Sandro,Fabrizi, Giancarlo
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p. 777 - 780
(2007/10/03)
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- Phase transfer Wittig reaction with 1,3-dioxolan-2-yl-methyltriphenyl phosphonium salts: An efficient method for vinylogation of aromatic aldehydes
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Aldehydes were efficiently transformed into allylic dioxolanes by a Wittig-type reaction, using 1,3-dioxolan-2-yl-methyltriphenylphosphonium bromide under phase transfer conditions. The substituent kinetic effects were studied, and related to Hammett values and electrochemical potentials.
- Daubresse, Nicolas,Francesch, Charlette,Rolando, Christian
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p. 10761 - 10770
(2007/10/03)
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- Modofied Borohydride Agents, (1,4-Diazabicyclooctane)(tetrahydroboronato)zinc Complex . A New Ligand Metal Borohydride as a Stable, Efficient, and Versatile Reducing Agent
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(1,4-Diazabicyclooctane)(tetrahydroborato)zinc complex is a stable compound which has been used for the selective reduction of aldehydes, ketones, α,β-unsaturated carbonyl compounds, α-diketones, acyloins and acyl chlorides to their alcohols and aldehydes in THF or CH2Cl2/hexane at room temperature or under reflux conditions.
- Firouzabadi, Habib,Zeynizadeh, Behzad
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p. 156 - 168
(2007/10/03)
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- "Vinylogs" and "acetylenylogs" of β-adrenergic agents
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Vinylogous (Groups III and V) and acetylenologous (Group IV) analogs of the classical β-adrenergic agents - stimulants and blockers - were prepared in order to evaluate the effect of degree of saturation, position of unsaturation and rigidity of the chain
- Nudelman, Abraham,Binnes, Yitschak,Shmueli-Broide, Naomi,Odessa, Yael,Hieble, J. Paul,Sulpizio, Anthony C.
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p. 125 - 132
(2007/10/03)
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- Hypoxic radiosensitizers: Substituted styryl derivatives
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A number of novel styryl epoxides, N-substituted-styryl-ethanolamines, N-mono and N,N'-bis-(2-hydroxyethyl)-cinnamamides - analogues to the known radiosensitizers RSU- 1069, pimonidazole and etanidazole - display selective hypoxic radiosensitizing activity. The styryl group, especially when substituted by electron withdrawing groups, was found to be bioisosteric to the nitroimidazolyl functionality. The most active derivative 2-(2'-nitrophenyl)ethen-1-yl-oxirane 8a displayed a sensitizer enhancement ratio (SER) of 5 relative to misonidazole.
- Nudelman,Falb,Odesa,Shmueli-Broide
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p. 619 - 625
(2007/10/02)
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- Rate of decarboxylation, monitored via the key enzyme-bound enamine, of conjugated α-keto acids by pyruvamide activated pyruvate decarboxylase is kinetically competent with turnover
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The rate of formation of the covalent thiamin diphosphate-bound enamine/C2-α-carbanion intermediate monitored at 440 nm from conjugated mechanism-based inhibitors of the structure (E)-YC6H4CH=CHCOCOOH, where Y = p-Cl, m-NO2, m-CF3, was determined in the absence and presence of the allosteric activator pyruvamide on brewers' yeast pyruvate decarboxylase (PDC, E.C. 4.1.1.1). For all three compounds the first-order rate constant for enamine formation was accelerated from 15-150-fold by conversion of the enzyme to its activated form. The rate constant for enamine formation is 102-103 times faster than those estimated for inactivation. Comparing the kcat (0.44 s-1) to the rate constant for decarboxylation (0.653 s-1) for Y = p-Cl leads one to conclude that enamine formation is kinetically competent to participate in the turnover pathway. Based on the maximum absorbance developed at 440 nm, and the ε= 104 at this wavelength for a model compound (Y = H), there appear to be four active sites per tetrameric holoenzyme. The kcat/active site for pyruvate is estimated at ca. 40 s-1 at 20°C, and the decarboxylation rate constant for pyruvate can be estimated to be 80 s-1 /active site at 20°C, assuming decarboxylation and product release are equal in kinetic significance. The rate constants for decarboxylation by activated PDC for Y = m-NO2, m-CF3 (53 and 69 s-1) are comparable to this estimated decarboxylation rate constant for pyruvate (80 s-1). The k's for Y = m-NO2, m-CF3 are also similar in magnitude to the decarboxylation rate constant (62-80 s-1 at 22°C) reported for pyruvate oxidase, an enzyme with considerable sequence homology to PDC, and one that follows the same mechanism through decarboxylation.
- Menon-Rudolph, Sunitha,Nishikawa, Sadakatsu,Zeng, Xiaoping,Jordan, Frank
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p. 10110 - 10112
(2007/10/02)
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