- Multiple catalytic aldolase antibodies suitable for chemical programming
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Chemical programming of nine murine antibodies with catalytic aldolase activity was examined using compounds, equipped with diketone or pro-vinyl ketone linkers that inhibit integrin adhesion receptor functions. The results showed that most Abs were progr
- Goswami, Rajib Kumar,Huang, Zheng-Zheng,Forsyth, Jane S.,Felding-Habermann, Brunhilde,Sinha, Subhash C.
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- Aldolase Cascade Facilitated by Self-Assembled Nanotubes from Short Peptide Amphiphiles
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Early evolution benefited from a complex network of reactions involving multiple C?C bond forming and breaking events that were critical for primitive metabolism. Nature gradually chose highly evolved and complex enzymes such as lyases to efficiently facilitate C?C bond formation and cleavage with remarkable substrate selectivity. Reported here is a lipidated short peptide which accesses a homogenous nanotubular morphology to efficiently catalyze C?C bond cleavage and formation. This system shows morphology-dependent catalytic rates, suggesting the formation of a binding pocket and registered enhancements in the presence of the hydrogen-bond donor tyrosine, which is exploited by extant aldolases. These assemblies showed excellent substrate selectivity and templated the formation of a specific adduct from a pool of possible adducts. The ability to catalyze metabolically relevant cascade transformations suggests the importance of such systems in early evolution.
- Afrose, Syed Pavel,Das, Dibyendu,Reja, Antara
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- A modular assembly strategy for improving the substrate specificity of small catalytic peptides
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In contrast to large proteins, small peptide catalysts typically display limited specificity for small molecule substrates. This is presumably a result of the limited opportunities small peptides have to fold in a manner that provides for the formation of an isolated reaction vessel that effectively binds and sequesters substrates from bulk solvent while at the same time catalyzing their transformation. For the preparation of small peptide catalysts that possess improved substrate specificity, we have developed a modular assembly strategy that involves appending phage display-derived substrate binding-domain modules to catalytically active peptide domains. We demonstrate the potential of this strategy with the construction of a small 35-amino acid residue aldolase peptide with improved substrate specificity. The advantages of this approach are that it reduces the demand on the functionalization of the catalytic site and it is modular, therefore making its adaptation to a variety of specificities rapid. The modular assembly strategy studied here may present advantages over exhaustive searches of large random-sequence peptide libraries for peptides with singular function. Copyright
- Tanaka, Fujie,Barbas III, Carlos F.
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- Active site plasticity of a computationally designed retro-aldolase enzyme
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RA110 is a computationally designed retro-aldolase enzyme that utilizes amine catalysis to convert 4-hydroxy-4-(6-methoxy-2-naphthyl)-2-butanone to 6-methoxy-2-naphthaldehyde and acetone. The original design accelerated substrate cleavage by a factor of 12 000 over background, and its activity was subsequently increased more than a thousand-fold by directed evolution. The X-ray structure of the evolved catalyst covalently modified with a 1,3-diketone inhibitor deviates substantially from the design model, however, with the ligand adopting a completely different orientation than predicted. Moreover, significant activity was maintained even after relocation of the reactive lysine within the apolar binding pocket. These results suggest that the success of the original design is not ascribable to atomically accurate molecular recognition, but rather to successful placement of a reactive lysine adjacent to an apolar binding pocket. Nevertheless, the stabilizing interactions observed at the active site of the evolved variant suggest that improvements in the precision of design calculations will afford enzymes with higher catalytic activities. What's that in your pocket? A computationally designed and experimentally optimized retro-aldolase enzyme utilizes amine catalysis for substrate cleavage. However, substantial differences between the original design model and experimental structure highlight the need for improved computational protocols. Generating catalysts with true enzyme-like activities will require more than simply placing a reactive lysine adjacent to a hydrophobic pocket.
- Obexer, Richard,Studer, Sabine,Giger, Lars,Pinkas, Daniel M.,Gruetter, Markus G.,Baker, David,Hilvert, Donald
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- Origins of catalysis by computationally designed retroaldolase enzymes
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We have investigated recently reported computationally designed retroaldolase enzymes with the goal of understanding the extent and the origins of their catalytic power. Direct comparison of the designed enzymes to primary amine catalysts in solution revealed a rate acceleration of 105-fold for the most active of the designed retroaldolases. Through pH-rate studies of the designed retroaldolases and evaluation of a Bronsted correlation for a series of amine catalysts, we found that lysine pKa values are shifted by 3-4 units in the enzymes but that the catalytic contributions fromthe shifted pKa values are estimated to be modest, about 10-fold. For the most active of the reported enzymes, we evaluated the catalytic contribution of two other design components: a motif intended to stabilize a bound water molecule and hydrophobic substrate binding interactions. Mutational analysis suggested that the bound water motif does not contribute to the rate acceleration. Comparison of the rate acceleration of the designed substrate relative to a minimal substrate suggested that hydrophobic substrate binding interactions contribute around 103-fold to the enzymatic rate acceleration. Altogether, these results suggest that substrate binding interactions and shifting the pKa of the catalytic lysine can account for much of the enzyme's rate acceleration. Additional observations suggest that these interactions are limited in the specificity of placement of substrate and active site catalytic groups. Thus, future design efforts may benefit from a focus on achieving precision in binding interactions and placement of catalytic groups.
- Lassila, Jonathan K.,Baker, David,Herschlag, Daniel
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- De Novo-designed enzymes as small-molecule-regulated fluorescence imaging tags and fluorescent reporters
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Enzyme-based tags attached to a protein-of-interest (POI) that react with a small molecule, rendering the conjugate fluorescent, are very useful for studying the POI in living cells. These tags are typically based on endogenous enzymes, so protein engineering is required to ensure that the small-molecule probe does not react with the endogenous enzyme in the cell of interest. Here we demonstrate that de novo-designed enzymes can be used as tags to attach to POIs. The inherent bioorthogonality of the de novo-designed enzyme - small-molecule probe reaction circumvents the need for protein engineering, since these enzyme activities are not present in living organisms. Herein, we transform a family of de novo-designed retroaldolases into variable-molecular-weight tags exhibiting fluorescence imaging, reporter, and electrophoresis applications that are regulated by tailored, reactive small-molecule fluorophores.
- Liu, Yu,Zhang, Xin,Tan, Yun Lei,Bhabha, Gira,Ekiert, Damian C.,Kipnis, Yakov,Bjelic, Sinisa,Baker, David,Kelly, Jeffery W.
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- Quantitative Packaging of Active Enzymes into a Protein Cage
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Genetic fusion of cargo proteins to a positively supercharged variant of green fluorescent protein enables their quantitative encapsulation by engineered lumazine synthase capsids possessing a negatively charged lumenal surface. This simple tagging system provides a robust and versatile means of creating hierarchically ordered protein assemblies for use as nanoreactors. The generality of the encapsulation strategy and its effect on enzyme function were investigated with eight structurally and mechanistically distinct catalysts.
- Azuma, Yusuke,Zschoche, Reinhard,Tinzl, Matthias,Hilvert, Donald
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- The influence of protein dynamics on the success of computational enzyme design
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We characterize the molecular dynamics of a previously described computational de novo designed enzyme optimized to perform a multistep retrol-aldol reaction when engineered into a TIM barrel protein scaffold. The molecular dynamics simulations show that
- Ruscio, Jory Z.,Kohn, Jonathan E.,Ball, K. Aurelia,Head-Gordon, Teresa
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- Preparation method of 6-methoxy-2-naphthaldehyde
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The invention discloses a preparation method of 6-methoxy-2-naphthaldehyde. The preparation method comprises the following step: carrying out a chemical reaction on 6-methoxy-2-acetonaphthone and a catalyst in an organic solvent, wherein gas is introduced when the reaction is started, a molar ratio of the 6-methoxy-2-acetonaphthone to the catalyst is 1: (0.01-10), a reaction temperature is 20-180 DEG C, and reaction time is 0.1-72 hours. According to the preparation method disclosed by the invention, no harsh reaction conditions such as high temperature and high pressure exist in a process route, the process route is simple, reaction conditions are mild, the raw materials are cheap and easy to obtain, operation is simple and convenient, and the preparation method is suitable for environment-friendly industrial production of the 6-methoxy-2-naphthaldehyde.
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Paragraph 0016-0035
(2021/11/19)
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- Engineered Artificial Carboligases Facilitate Regioselective Preparation of Enantioenriched Aldol Adducts
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Controlling regio- A nd stereoselectivity of aldol additions is generally challenging. Here we show that an artificial aldolase with high specificity for acetone as the aldol donor can be reengineered via single active site mutations to accept linear and cyclic aliphatic ketones with notable efficiency, regioselectivity, and stereocontrol. Biochemical and crystallographic data show how the mutated residues modulate the binding and activation of specific aldol donors, as well as their subsequent reaction with diverse aldehyde acceptors. Broadening the substrate scope of this evolutionarily na?ve catalyst proved much easier than previous attempts to redesign natural aldolases, suggesting that such proteins may be excellent starting points for the development of customized biocatalysts for diverse practical applications.
- MacDonald, Duncan S.,Garrabou, Xavier,Klaus, Cindy,Verez, Rebecca,Mori, Takahiro,Hilvert, Donald
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supporting information
p. 10250 - 10254
(2020/09/21)
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- Continuous flow synthesis of aryl aldehydes by Pd-catalyzed formylation of phenol-derived aryl fluorosulfonates using syngas
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This communication describes the palladium-catalyzed reductive carbonylation of aryl fluorosulfonates (ArOSO2F) using syngas as an inexpensive and sustainable source of carbon monoxide and hydrogen. The conversion of phenols to aryl fluorosulfonates can be conveniently achieved by employing the inexpensive commodity chemical sulfuryl fluoride (SO2F2) and base. The developed continuous flow formylation protocol requires relatively low loadings for palladium acetate (1.25 mol%) and ligand (2.5 mol%). Good to excellent yields of aryl aldehydes were obtained within 45 min for substrates containing electron withdrawing substituents, and 2 h for substrates containing electron donating substituents. The optimal reaction conditions were identified as 120 °C temperature and 20 bar pressure in dimethyl sulfoxide (DMSO) as solvent. DMSO was crucial in suppressing Pd black formation and enhancing reaction rate and selectivity. This journal is
- Hanselmann, Paul,Hone, Christopher A.,Hu, Guixian,K?ckinger, Manuel,Kappe, C. Oliver
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p. 22449 - 22453
(2020/07/03)
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- Substrate and inhibitor selectivity, and biological activity of an epoxide hydrolase from Trichoderma reesei
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Epoxide hydrolases (EHs) are present in all living organisms and catalyze the hydrolysis of epoxides to the corresponding vicinal diols. EH are involved in the metabolism of endogenous and exogenous epoxides, and thus have application in pharmacology and biotechnology. In this work, we describe the substrates and inhibitors selectivity of an epoxide hydrolase recently cloned from the filamentous fungus Trichoderma reesei QM9414 (TrEH). We also studied the TrEH urea-based inhibitors effects in the fungal growth. TrEH showed high activity on radioative and fluorescent surrogate and natural substrates, especially epoxides from docosahexaenoic acid. Using a fluorescent surrogate substrate, potent inhibitors of TrEH were identified. Interestingly, one of the best compounds inhibit up to 60% of T. reesei growth, indicating an endogenous role for TrEH. These data make TrEH very attractive for future studies about fungal metabolism of fatty acids and possible development of novel drugs for human diseases.
- de Oliveira, Gabriel S.,Adriani, Patricia P.,Wu, Hao,Morisseau, Christophe,Hammock, Bruce D.,Chambergo, Felipe S.
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p. 371 - 379
(2018/11/23)
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- Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed Formylation of Aryl Bromides Using Carbon Monoxide and Hydrogen
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A continuous-flow protocol utilizing syngas (CO and H2) was developed for the palladium-catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and residence time resulted in process-intensified flow conditions for the transformation. In addition, a key benefit of investigating the reaction in flow is the ability to precisely control the CO-to-H2 stoichiometric ratio, which was identified as having a critical influence on yield. The protocol proceeds with low catalyst and ligand loadings: palladium acetate (1 mol % or below) and cataCXium A (3 mol % or below). A variety of (hetero)aryl bromides at a 3 mmol scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H2=1:3) and 120 °C reaction temperature within 45 min residence time to afford products mostly in good-to-excellent yields (17 examples). In particular, a successful scale-up was achieved over 415 min operation time for the reductive carbonylation of 2-bromo-6-methoxynaphthalene to synthesize 3.8 g of 6-methoxy-2-naphthaldehyde in 85 % isolated yield. Studies were conducted to understand catalyst decomposition within the reactor by using inductively coupled plasma–mass spectrometry (ICP–MS) analysis. The palladium could easily be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the scope of the transformation are discussed.
- Hone, Christopher A.,Lopatka, Pavol,Munday, Rachel,O'Kearney-McMullan, Anne,Kappe, C. Oliver
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p. 326 - 337
(2018/11/23)
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- A conjugated system of curcumin analogs increase and its preparation method and application
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The invention discloses a curcumin analogue with an enlarged conjugated system and a preparation method and application thereof. The structural feature of the curcumin analogue is shown in the general formula (I), wherein R1 is hydrogen and methoxyl, R2 is hydrogen, hydroxy and methoxyl, and two naphthalene nucleuses are connected through a 1,6-heptadiene-3,5-diketone joining chain. The naphthol is used as a raw material, the naphthalene nucleus curcumin analogue with the superior activity for hepatoma carcinoma cell HepG2 cell proliferation is synthesized, and the activity of the curcumin analogue is superior to that of natural curcumin. The curcumin analogue with the enlarged conjugated system has the great significance in guiding discovery of prodrugs and designing lead compounds.
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- Optimization of Enzyme Mechanism along the Evolutionary Trajectory of a Computationally Designed (Retro-)Aldolase
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De novo biocatalysts have been successfully generated by computational design and subsequent experimental optimization. Here, we examined the evolutionary history of the computationally designed (retro-)aldolase RA95. The modest activity of the starting enzyme was previously improved 105-fold over many rounds of mutagenesis and screening to afford a proficient biocatalyst for enantioselective cleavage and synthesis of β-hydroxyketones. Using a set of representative RA95 variants, we probed individual steps in the multistep reaction pathway to determine which processes limit steady-state turnover and how mutations that accumulated along the evolutionary trajectory influenced the kinetic mechanism. We found that the overall rate-limiting step for aldol cleavage shifted from C-C bond scission (or an earlier step in the pathway) for the computational design to product release for the evolved enzymes. Specifically, interconversion of Schiff base and enamine intermediates, formed covalently between acetone and the catalytic lysine residue, was found to be the slowest step for the most active variants. A complex hydrogen bond network of four active site residues, which was installed in the late stages of laboratory evolution, apparently enhances lysine reactivity and facilitates efficient proton shuffling. This catalytic tetrad accounts for the tremendous rate acceleration observed for all steps of the mechanism, most notably Schiff base formation and hydrolysis. Comparison of our results with kinetic and structural studies on natural aldolases provides valuable feedback for computational enzyme design and laboratory evolution approaches alike.
- Zeymer, Cathleen,Zschoche, Reinhard,Hilvert, Donald
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supporting information
p. 12541 - 12549
(2017/09/23)
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- Emergence of a catalytic tetrad during evolution of a highly active artificial aldolase
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Designing catalysts that achieve the rates and selectivities of natural enzymes is a long-standing goal in protein chemistry. Here, we show that an ultrahigh-throughput droplet-based microfluidic screening platform can be used to improve a previously optimized artificial aldolase by an additional factor of 30 to give a >10 9 rate enhancement that rivals the efficiency of class I aldolases. The resulting enzyme catalyses a reversible aldol reaction with high stereoselectivity and tolerates a broad range of substrates. Biochemical and structural studies show that catalysis depends on a Lys-Tyr-Asn-Tyr tetrad that emerged adjacent to a computationally designed hydrophobic pocket during directed evolution. This constellation of residues is poised to activate the substrate by Schiff base formation, promote mechanistically important proton transfers and stabilize multiple transition states along a complex reaction coordinate. The emergence of such a sophisticated catalytic centre shows that there is nothing magical about the catalytic activities or mechanisms of naturally occurring enzymes, or the evolutionary process that gave rise to them.
- Obexer, Richard,Godina, Alexei,Garrabou, Xavier,Mittl, Peer R. E.,Baker, David,Griffiths, Andrew D.,Hilvert, Donald
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- A Well-Defined Osmium-Cupin Complex: Hyperstable Artificial Osmium Peroxygenase
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Thermally stable TM1459 cupin superfamily protein from Thermotoga maritima was repurposed as an osmium (Os) peroxygenase by metal-substitution strategy employing the metal-binding promiscuity. This novel artificial metalloenzyme bears a datively bound Os ion supported by the 4-histidine motif. The well-defined Os center is responsible for not only the catalytic activity but also the thermodynamic stability of the protein folding, leading to the robust biocatalyst (Tm ≈ 120 °C). The spectroscopic analysis and atomic resolution X-ray crystal structures of Os-bound TM1459 revealed two types of donor sets to Os center with octahedral coordination geometry. One includes trans-dioxide, OH, and mer-three histidine imidazoles (O3N3 donor set), whereas another one has four histidine imidazoles plus OH and water molecule in a cis position (O2N4 donor set). The Os-bound TM1459 having the latter donor set (O2N4 donor set) was evaluated as a peroxygenase, which was able to catalyze cis-dihydroxylation of several alkenes efficiently. With the low catalyst loading (0.01% mol), up to 9100 turnover number was achieved for the dihydroxylation of 2-methoxy-6-vinyl-naphthalene (50 mM) using an equivalent of H2O2 as oxidant at 70 °C for 12 h. When octene isomers were dihydroxylated in a preparative scale for 5 h (2% mol cat.), the terminal alkene octene isomers was converted to the corresponding diols in a higher yield as compared with the internal alkenes. The result indicates that the protein scaffold can control the regioselectivity by the steric hindrance. This protein scaffold enhances the efficiency of the reaction by suppressing disproportionation of H2O2 on Os reaction center. Moreover, upon a simple site-directed mutagenesis, the catalytic activity was enhanced by about 3-fold, indicating that Os-TM1459 is evolvable nascent osmium peroxygenase.
- Fujieda, Nobutaka,Nakano, Takumi,Taniguchi, Yuki,Ichihashi, Haruna,Sugimoto, Hideki,Morimoto, Yuma,Nishikawa, Yosuke,Kurisu, Genji,Itoh, Shinobu
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supporting information
p. 5149 - 5155
(2017/05/04)
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- Regioselective Copper-Catalyzed Boracarboxylation of Vinyl Arenes
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Regioselective copper-catalyzed boracarboxylation of vinyl arenes with bis(pinacolato)diboron and carbon dioxide has been achieved. New boron-functionalized α-aryl carboxylic acids, including nonsteroidal anti-inflammatory drugs (NSAIDs), are obtained in moderate to excellent yields. The synthetic utility of the transformation was shown through subsequent derivatization of the carbon-boron bond yielding formal hydroxy- and fluorocarboxylation products as well as anionic difluoroboralactones.
- Butcher, Trevor W.,McClain, Edward J.,Hamilton, Tyler G.,Perrone, Trina M.,Kroner, Kayla M.,Donohoe, Gregory C.,Akhmedov, Novruz G.,Petersen, Jeffrey L.,Popp, Brian V.
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supporting information
p. 6428 - 6431
(2016/12/23)
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- Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus
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The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA-binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function.
- Tarus, Bogdan,Bertrand, Hélène,Zedda, Gloria,Di Primo, Carmelo,Quideau, Stéphane,Slama-Schwok, Anny
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p. 1899 - 1912
(2015/02/19)
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- Palladium-catalyzed carbonylations of aryl bromides using paraformaldehyde: Synthesis of aldehydes and esters
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Carbonylation reactions represent useful tools for organic synthesis. However, the necessity to use gaseous carbon monoxide is a disadvantage for most organic chemists. To solve this problem, novel protocols have been developed for conducting palladium-catalyzed reductive carbonylations of aryl bromides and alkoxycarbonylations using paraformaldehyde as an external CO source (CO gas free). Hence, aromatic aldehydes and esters were synthesized in moderate to good yields.
- Natte, Kishore,Dumrath, Andreas,Neumann, Helfried,Beller, Matthias
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supporting information
p. 10090 - 10094
(2015/03/31)
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- Evaluation of synthetic naphthalene derivatives as novel chemical chaperones that mimic 4-phenylbutyric acid
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The chemical chaperone 4-phenylbutyric acid (4-PBA) has potential as an agent for the treatment of neurodegenerative diseases. However, the requirement of high concentrations warrants chemical optimization for clinical use. In this study, novel naphthalene derivatives with a greater chemical chaperone activity than 4-PBA were synthesized with analogy to the benzene ring. All novel compounds showed chemical chaperone activity, and 2 and 5 possessed high activity. In subsequent experiments, the protective effects of the compounds were examined in Parkinson's disease model cells, and low toxicity of 9 and 11 was related to amphiphilic substitution with naphthalene.
- Mimori, Seisuke,Koshikawa, Yukari,Mashima, Yu,Mitsunaga, Katsuyoshi,Kawada, Koichi,Kaneko, Masayuki,Okuma, Yasunobu,Nomura, Yasuyuki,Murakami, Yasuoki,Kanzaki, Tetsuto,Hamana, Hiroshi
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p. 811 - 814
(2015/02/19)
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- Carbon-Carbon bond cleavage in activation of the prodrug nabumetone
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Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17b-lyase (CYP17), and aromatase (CYP19). Because of the high substrate specificities of these enzymes and the complex nature of their substrates, these reactions have been difficult to characterize. A CYP1A2-catalyzed carbon-carbon bond cleavage reaction is required for conversion of the prodrug nabumetone to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). Despite worldwide use of nabumetone as an anti-inflammatory agent, the mechanism of its carbon-carbon bond cleavage reaction remains obscure. With the help of authentic synthetic standards, we report here that the reaction involves 3-hydroxylation, carbon-carbon cleavage to the aldehyde, and oxidation of the aldehyde to the acid, all catalyzed by CYP1A2 or, less effectively, by other P450 enzymes. The data indicate that the carbon-carbon bond cleavage is mediated by the ferric peroxo anion rather than the ferryl species in the P450 catalytic cycle. CYP1A2 also catalyzes O-demethylation and alcohol to ketone transformations of nabumetone and its analogs.
- Varfaj, Fatbardha,Zulkifli, Siti N. A.,Park, Hyoung-Goo,Challinor, Victoria L.,De Voss, James J.,De Montellano, Paul R. Ortiz
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p. 828 - 838
(2014/05/06)
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- Heteroatom-free arene-cobalt and arene-iron catalysts for hydrogenations
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75 years after the discovery of hydroformylation, cobalt catalysts are now undergoing a renaissance in hydrogenation reactions. We have evaluated arene metalates in which the low-valent metal species is - conceptually different from heteroatom-based ligands - stabilized by π coordination to hydrocarbons. Potassium bis(anthracene)cobaltate 1 and -ferrate 2 can be viewed as synthetic precursors of quasi-"naked" anionic metal species; their aggregation is effectively impeded by (labile) coordination to the various π acceptors present in the hydrogenation reactions of unsaturated molecules (alkenes, arenes, carbonyl compounds). Kinetic studies, NMR spectroscopy, and poisoning studies of alkene hydrogenations support the formation of a homogeneous catalyst derived from 1 which is stabilized by the coordination of alkenes. This catalyst concept complements the use of complexes with heteroatom donor ligands for reductive processes. Especially high selectivities were observed in the hydrogenation of various alkenes, ketones, and imines with bis(anthracene) cobaltate(-I) [K(dme)2{Co(C14H10)2}] under mild conditions (1-5 mol% cat., 1-10 bar H2, 20-60°C). Mechanistic studies indicate the operation in alkene hydrogenations of a homogeneous catalyst formed by initial ligand exchange and stabilized by the coordination of π-acidic alkenes or arenes.
- Gaertner, Dominik,Welther, Alice,Rad, Babak Rezaei,Wolf, Robert,Von Wangelin, Axel Jacobi
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supporting information
p. 3722 - 3726
(2014/04/17)
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- 2-Iodoxybenzenesulfonic acid-catalysed oxidation of primary and secondary alcohols with oxone in cetyl trimethylammonium bromide micelles at room temperature
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A mild and green protocol for alcohol oxidation using 2-iodoxybenzene sulfonic acid/oxone at room temperature in CTAB micelles has been developed. Typically, secondary benzyl alcohols were oxidised to ketones and primary benzyl alcohols to aldehydes in good yields in 2 h. Under harsher conditions (100 °C/24 h), aliphatic alcohols were oxidised to ketones or organic acids in moderate to high yields.
- Liu, Yangyang,Wang, Boliang
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p. 427 - 431
(2014/08/05)
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- CATECHOL O-METHYLTRANSFERASE ACTIVITY INHIBITING COMPOUNDS
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Compounds of formula (I), wherein R1 is as defined in the claims, exhibit COMT enzyme inhibiting activity and are thus useful as COMT inhibitors.
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Page/Page column 124
(2014/01/07)
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- Chemically programmed antibodies as HIV-1 attachment Inhibitors
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Herein, we describe the design and application of two small-molecule anti-HIV compounds for the creation of chemically programmed antibodies. N-Acyl-β-lactam derivatives of two previously described molecules BMS-378806 and BMS-488043 that inhibit the interaction between HIV-1 gp120 and T-cells were synthesized and used to program the binding activity of aldolase antibody 38C2. Discovery of a successful linkage site to BMS-488043 allowed for the synthesis of chemically programmed antibodies with affinity for HIV-1 gp120 and potent HIV-1 neutralization activity. Derivation of a successful conjugation strategy for this family of HIV-1 entry inhibitors enables its application in chemically programmed antibodies and vaccines and may facilitate the development of novel bispecific antibodies and topical microbicides.
- Sato, Shinichi,Inokuma, Tsubasa,Otsubo, Nobumasa,Burton, Dennis R.,Barbas, Carlos F.
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p. 460 - 465
(2013/07/25)
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- Palladium-catalyzed reductive carbonylation of aryl bromides with phosphinite ligands
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A palladium-catalyzed reductive carbonylation of aryl bromides into the corresponding aryl aldehydes has been described using synthesis gas in the presence of phosphinite ligands. Several products have been synthesized in moderate to good yields (35-97 %) under mild reaction conditions. Copyright
- Neumann, Helfried,Kadyrov, Renat,Wu, Xiao-Feng,Beller, Matthias
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p. 2213 - 2216
(2012/10/29)
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- Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors
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A series of naphthylisopropylamine and N-benzyl-4-methylthioamphetamine derivatives were evaluated as monoamine oxidase inhibitors. Their potencies were compared with those of a series of amphetamine derivatives, to test if the increase of electron richness of the aromatic ring and overall size of the molecule might improve their potency as enzyme inhibitors. Molecular dockings were performed to gain insight regarding the binding mode of these inhibitors and rationalize their different potencies. In the case of naphthylisopropylamine derivatives, the increased electron-donating capacity and size of the aromatic moiety resulting from replacement of the phenyl ring of amphetamine derivatives by a naphthalene system resulted in more potent compounds. In the other case, extension of the arylisopropylamine molecule by N-benzylation of the amino group led to a decrease in potency as monoamine oxidase inhibitors.
- Vilches-Herrera, Marcelo,Miranda-Sepulveda, Juan,Rebolledo-Fuentes, Marco,Fierro, Angelica,Luehr, Susan,Iturriaga-Vasquez, Patricio,Cassels, Bruce K.,Reyes-Parada, Miguel
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experimental part
p. 2452 - 2460
(2009/09/08)
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- Discovery of a sensitive, selective, and tightly binding fluorogenic substrate of bovine plasma amine oxidase
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(Chemical Equation Presented) We report a novel fluorogenic substrate of bovine plasma amine oxidase (BPAO), namely, (2-(6-(aminomethyl)naphthalen-2- yloxy)ethyl)trimethylammonium (ANETA), which displays extremely tight binding to BPAO (Km 183 ± 14 nM) and yet is metabolized fairly quickly (kcat 0.690 ± 0.010 s-1), with the aldehyde turnover product (2-(6-formylnaphthalen-2-yloxy)ethyl)trimefhylammonium serving as a real time reporting fluorophore of the enzyme activity. This allowed for the development of a fluorometric noncoupled assay that is 2 orders of magnitude more sensitive than the spectrophotometric benzylamine assay. The discovery of ANETA involved elaboration of the lead compound 6-methoxy-2-naphthalene- methaneamine by structure-based design, which recognized the ancillary cation binding site of BPAO as the most significant structural features controlling binding affinity. Structure-based design further ensured a high level of selectivity: ANETA is a good substrate of BPAO but is not a substrate of either porcine kidney diamine oxidase (pkDAO) or rat liver monoamine oxidase (MAO-B). ANETA represents the first highly sensitive, selective, and tight binding fluorogenic substrate of a copper amine oxidase that is able to respond directly to the enzyme activity in real time.
- Ling, Ke-Qing,Sayre, Lawrence M.
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experimental part
p. 339 - 350
(2009/04/11)
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- An efficient chemical approach to bispecific antibodies and antibodies of high valency
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Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with β-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (d-Lys6)-LHRH or ano
- Gavrilyuk, Julia I.,Wuellner, Ulrich,Salahuddin, Syed,Goswami, Rajib K.,Sinha, Subhash C.,Barbas III, Carlos F.
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supporting information; experimental part
p. 3716 - 3720
(2010/02/28)
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- Palladium/di-1-adamantyl-n-butylphosphine-catalyzed reductive carbonylation of aryl and vinyl halides
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A general and efficient palladium-catalyzed reductive carbonylation with low catalyst loadings (0.5 mol % Pd or below) has been developed. The formylation of aryl and heteroaryl bromides proceeds smoothly in the presence of palladium/di-1-adamantyl-n-butylphosphine at ambient pressure of synthesis gas to afford the corresponding aromatic aldehydes in good yields and excellent selectivity. In addition, vinyl halides react under similar conditions to form α,β-unsaturated aldehydes in good yield.
- Brennführer, Anne,Neumann, Helfried,Klaus, Stefan,Riermeier, Thomas,Almena, Juan,Beller, Matthias
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p. 6252 - 6258
(2008/02/04)
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- A general and efficient method for the formylation of aryl and heteroaryl bromides
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(Chemical Equation Presented) The key to the general and efficient palladium-catalyzed formylation of aryl and heteroaryl bromides is the use of the di-1-adamantyl-n-butylphosphane (cataC-Xium A) as ligand. Low pressure of the synthesis gas and appropriate choice of the base are also important for high yields (up to 99%) of a broad range of (hetero)aromatic aldehydes at unprecedented low catalyst concentrations (see scheme; TMEDA= N,N,N′,N′-tetramethylethylenediamine).
- Klaus, Stefan,Neumann, Helfried,Zapf, Alexander,Struebing, Dirk,Huebner, Sandra,Almena, Juan,Riermeier, Thomas,Gross, Peter,Sarich, Martin,Krahnert, Wolf-Ruediger,Rossen, Kai,Beller, Matthias
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p. 154 - 158
(2007/10/03)
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- In vitro evaluation of the anti-estrogenic activity of hydroxyl substituted diphenylnaphthyl alkene ligands for the estrogen receptor
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There is still a need for additional scaffolds to further explore tissue selectivity and improving efficacy of selective estrogen receptor modulators (SERMs). A series of hydroxyl substituted diphenylnaphthyl alkene ligands for the two estrogen receptors are described that arose from an initial de novo designed diphenylnaphthyl propylene ligand 1. All compounds gave Kis under 10 nM when assayed in the presence of ERα. Generally these compounds had very high affinity for both ER isotypes. Moving the hydroxyl group on naphthalene from the 6- to the 5-position of the α-naphthalene attached compounds (6b and 6e vs 6c and 6f) had little affect on ER binding nor did altering the position of the naphthalene attachment (α or β) to the alkene moiety. In transfection assays none of the compounds displayed agonistic activity in the absence of E2. In MCF-7 proliferation assays 6a-d, 6f and 12a-c successfully abrogated E2 stimulation and resulted in greater than 50% inhibition at 1 μM, a level of efficacy similar to that obtained when the cells were treated with raloxifene. Our results show that this new class of SERMs are good candidates for further study as therapeutic agents for the treatment of breast cancer and osteoporosis.
- Schmidt, Jonathan M.,Tremblay, Gilles B.,Plastina, Michael A.,Ma, Fupeng,Bhal, Sanjivanjit,Feher, Miklos,Dunn-Dufault, Robert,Redden, Peter R.
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p. 1819 - 1828
(2008/02/02)
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- A catalytic asymmetric bioorganic route to enantioenriched tetrahydro- and dihydropyranones
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A conceptually novel approach to hetero Diels-Alder adducts of carbonyl compounds is described using as the key steps an antibody-mediated kinetic resolution of hydroxyenones followed by a ring-closure process. Various β-hydroxyenones proved to be very good substrates for antibodies 84G3- and 93F3-catalyzed retro-aldol reactions, allowing the preparation of highly enantiomerically enriched (up to 99% ee) precursors of pyranones. An attractive feature of this methodology is the possibility to convert these acyclicenantioenriched β-hydroxyenones into tetrahydropyranones by a conventional Michael-type addition procedure or into the corresponding dihydropyranones using an alternative palladium-catalyzed oxidative ring closure. For the palladium-mediated cyclization, a biphasic system has been implemented that allows the direct preparation of enantiopure dihydropyranones from the corresponding racemic aldol precursors using a sequential antibody-resolution/palladium-cyclization strategy, without isolation of the intermediate enantioenriched hydroxyenones. This bioorganic route is best applied to the preparation of hetero Diels-Alder adducts otherwise derived from less nucleophilic dienes and unactivated dienophiles.
- Baker-Glenn, Charles,Hodnett, Neil,Reiter, Maud,Ropp, Sandrine,Ancliff, Rachael,Gouverneur, Veronique
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p. 1481 - 1486
(2007/10/03)
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- C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors
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A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C17,20-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C 17,20-lyase over 11β-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.
- Matsunaga, Nobuyuki,Kaku, Tomohiro,Ojida, Akio,Tanaka, Toshimasa,Hara, Takahito,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
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p. 4313 - 4336
(2007/10/03)
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- Chemical partitioning agents and methods of using same
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The present invention is directed to partitioning agents and methods of using same to effectuate separation of a reactant, intermediate product, and/or final product from a reaction mixture while minimizing the need for traditional separation or isolation techniques.
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Page column 13-14
(2010/02/05)
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- Method for releasing a product comprising chemical oxidation, method for detecting said product and uses thereof
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This invention has as its object a method for releasing a product by subjecting a compound of Formula (II′): R′7R′8(HX)C1-C2(YH)R′9R′10 to a chemical oxidation that cleaves the bond C1-C2 to obtain the product. In the compound of Formula (II′): R′7 to R′10, which are identical or different, correspond to a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted functional group; X and Y, which are identical or different, are an oxygen atom, a sulfur atom, or an amine of Formula -NR11R12, wherein R11 is a hydrogen atom, an alkyl group, or a substituted or unsubstituted aryl group, and R12 is not a hydrogen atom. The invention also has as its object a method for releasing a product that comprises, before the chemical oxidation stage, a first step for preparing the compound of Formula (II′). The released product can be a volatile molecule or an active substance or else a specific product. The invention also relates to a method for detecting the released product as well as its applications, in particular for detecting catalytic or enzymatic activities.
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- Electroorganic reactions. Part 56: Anodic oxidation of 2-methyl- and 2-benzylnaphthalenes: Factors influencing competing pathways
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A systematic investigation of the anodic oxidation in nucleophilic media of 2-methyl and 2-benzylnaphthalenes, substituted at the 6-position in the naphthalene nucleus and at the 4-phenyl position of the benzylic side chain, has been carried out to identify factors favouring side-chain substitution. Cyclic voltammetry confirms that 6-substitution has a profound effect on the oxidation potentials of the naphthalene nucleus and 13C chemical shifts indicate polar effects at the benzylic carbon. However, little side-chain anodic oxidation is observed under any conditions tried; the radical-cations of electron-rich substrates preferentially dimerise and a strongly electron-withdrawing substituent at the 6-position (EtOSO2) promotes nuclear substitution. In contrast, oxidation with DDQ in aqueous acetic acid gives efficient side-chain oxidation for electron rich substrates, consistent with hydride transfer, possibly intramolecularly via a charge transfer complex.
- Utley, James H.P,Rozenberg, Gregor G
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p. 5251 - 5265
(2007/10/03)
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- Fused ring compounds, process for producing the same and use thereof
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To provide a novel compound of the formula: [wherein A1 ix a 5 or 6-membered ring which may be substituted by a group not containing a cyclic group, A2 is an aromatic ring which may be substituted, X is a divalent group, Y is a nitrogen atom or a methine group, Z is an ethenylene which may be substituted or ethynylene, R is a heterocyclic group which may be substituted, provided that 3,4-dihydro-6-[3-(1H-imidazol-1-yl)-1-propenyl]-2(1H)-quinolone and 2-[3-[5-ethyl-6-methyl-2-(benzyloxy)-3-pyridyl]-1-propenyl]benzoxazole are excluded.], or a salt thereof which has steroid C17,20-lyase inhibitory activity, and is useful for preventing and treating mammals suffering from, for example, primary cancer of malignant tumor, its metastasis and recurrence thereof.
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- Enzyme fingerprints of activity, and stereo- and enantioselectivity from fluorogenic and chromogenic substrate arrays
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A series of stereochemically and structurally diverse fluorogenic and chromogenic substrates for hydrolytic enzymes has been synthesized and used to characterize enzyme activity profiles of esterases, lipases, proteases, peptidases, phosphatases, and epoxide hydrolases. The substrates used are particularly resilient to nonspecific reactions due to their mechanism of activation. The activities recorded with the individual substrates are therefore remarkably reproducible, and enable us to use the overall pattern of activity as a specific fingerprint for the enzyme sample. Fingerprints of activity, and enantio- and stereoselectivity are displayed as arrays of color-scale squares that are easily analyzed visually. Such fingerprints might be useful for quality control, enzyme discovery, and possibly for addressing the issue of functional convergence in enzymes.
- Wahler, Denis,Badalassi, Fabrizio,Crotti, Paolo,Reymond, Jean-Louis
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p. 3211 - 3228
(2007/10/03)
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- Phage display selection of peptides possessing aldolase activity
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Peptides catalyzing retro-aldol reactions were selected from a phage display peptide library using 1,3-diketones designed for the covalent selection of an enamine-based reaction mechanism.
- Tanaka,Barbas III
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p. 769 - 770
(2007/10/03)
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- A photophysical and photochemical study of 6-methoxy-2-naphthylacetic acid, the major metabolite of the phototoxic nonsteroidal antiinflammatory drug nabumetone
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Nabumetone is a phototoxic nonsteroidal antiinflammatory drug used for the treatment of osteoarthritis. However, nabumetone is considered a prodrug with its metabolite 6-methoxy-2-naphthylacetic acid the active form. Photophysical and photochemical studies on this metabolite have been undertaken. It undergoes photodecarboxylation in aerated aqueous and organic solvents. In addition to the accepted photodegradation pathway for related molecules, a new mechanism that implies generation of the naphthalene radical cation from the excited singlet and addition of O2 prior to the decarboxylation process has been demonstrated. Evidence for the involvement of the excited singlet state in this mechanism have been obtained by steady-state and time-resolved fluorescence experiments. The fluorescence quenching by O2 and the shorter singlet lifetime in aerated solvents support this assignment. Laser flash photolysis also supports this mechanism by showing the noninvolvement of the triplet in the formation of the naphthalene radical cation. Finally, the well-known electron acceptor CCl4 acts as an efficient singlet quencher, enhancing the route leading to the radical cation, preventing intersystem crossing to the triplet and thus resulting in a dramatic increase in the yield of 6-methoxy-2-naphthaldehyde, the major oxidative decarboxylation product; this constitutes unambiguous proof in favor of the new mechanistic proposals.
- Bosca,Canudas,Marin,Miranda
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p. 173 - 177
(2007/10/03)
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- Tetrabutylammonium peroxydisulfate in organic synthesis; VII. A facile and efficient method for the regeneration of carbonyl compounds from semicarbazones by tetrabutylammonium peroxydisulfate
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Semicarbazones of aldehydes and ketones are oxidized to the corresponding carbonyl compounds in excellent yields by tetrabutylammonium peroxydisulfate in dichlorlethane under mild conditions.
- Chen, Fen-Er,Liu, Ji-Dong,Fu, Han,Peng, Zuo-Zhong,Shao, Lan-Ying
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p. 2295 - 2299
(2007/10/03)
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- Tetrabutylammonium peroxydisulfate in organic synthesis; IV. An efficient, highly selective and oxidative deoximation by tetrabutylammonium peroxydisulfate
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Tetrabutylammonium peroxydisulfate has been proved out to be an efficient and highly chemoselective reagent for the conversion of oximes to the corresponding carbonyl compounds under mild conditions.
- Chen, Fener,Liu, Anchang,Yan, Qiongjiao,Liu, Mingxing,Zhang, Daoming,Shao, Lanying
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p. 1049 - 1056
(2007/10/03)
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- Process research and structural studies on nabumetone
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A short, simple and economical process for large-scale preparation of nabumetone has been developed. The single-crystal structures of nabumetone and one of its key intermediates have been determined by X-ray diffraction studies. Two impurities have been isolated and characterised.
- Prabhakar,Reddy, C. Bakki,Reddy, Ch. Maheedhara,Nageshwar,Devi, A. Sivalakshmi,Babu, J. Moses,Vyas,Sarma,Reddy
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p. 121 - 125
(2013/09/08)
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- Broadening the aldolase catalytic antibody repertoire by combining reactive immunization and transition state theory: New enantio- and diastereoselectivities
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Nine efficient aldolase antibodies were generated by using hapten 1. This hapten unites reactive immunization and the transition state analogue approach in a single molecule. Characterization of two of these antibodies reveals that they are highly proficient (up to 1000-fold better than any other antibody catalyst) and enantioselective catalysts for aldol and retro- aldol reactions and exhibit enantio-and diastereoselectivities opposite to that of antibody 38C2.
- Zhong, Guofu,Lerner, Richard A.,Barbas III, Carlos F.
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p. 3738 - 3741
(2007/10/03)
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- Production of nabumetone or precursors thereof
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In producing nabumetone or precursor thereof, use is made of 2-bromo-6-methoxynaphthalene formed by (a) methylating 6-bromo-2-naphthol with methyl bromide or methyl chloride, in a halogen-free liquid solvent comprising at least about 40% by weight of one or more compounds of the formula RZ where R is a hydrogen atom or an alkyl group, and Z is a hydroxyl group or a cyanide group with the proviso that if Z is a cyanide group, R is an alkyl group, and in the presence of at least one strong base; and (b) recovering and purifying 2-bromo-6-methoxynaphthalene so formed. The 6-bromo-2-naphthol in turn is preferably formed by reacting 1,6-dibromo-2-naphthol with hydrogen in a halogen-containing liquid solvent comprising at least about 50% by weight of (A) at least one liquid organic halide solvent in which the halogen content has an atomic number of 35 or less or (B) a mixture of water and at least one such liquid organic halide solvent, and in the presence of catalytic amounts of (i) a tungsten carbide-based catalyst, and (ii) at least one phase transfer catalyst, most preferably while purging HBr from the reaction mixture as it is formed. In this way, the quantities of by-products formed in the overall operation are reduced, the need for use of excess iron and/or dimethyl sulfate as reaction components is avoided, and the overall efficiency of plant operation is improved especially when conducted on a large scale.
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- Fluorine-substituted derivatives of the carcinogenic dihydrodiol and diol epoxide metabolites of 7-methyl-, 12-methyl- and 7,12-dimethylbenz[a]anthracene
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Stereospecific syntheses of the trans-3,4-dihydrodiol metabolites of 9- and 10-fluoro-7, 12-dimethylbenz[alanthracene, -7-methylbenz[a]anthracene, and -12-methylbenz[a]anthracene are described. These dihydrodiols are putative proximate carcinogenic metabolites that undergo activation by the P-450 microsomal enzymes to ultimate carcinogenic anti- and syn-diol epoxide metabolites that bind to nucleic acids in vivo. Syntheses of several of the anti- diol epoxide metabolites are also described.
- Harvey, Ronald G.,Cortez, Cecilia
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p. 7101 - 7118
(2007/10/03)
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- ALPHA-MERCAPTOACRYLIC ACID DERIVATIVES HAVING CALPAIN INHIBITORY ACTIVITY
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The invention covers a novel series of α-mercaptoacrylic acid derivatives that inhibit both calpain I and calpain II with a high affinity and selectivity. The compounds are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders, brain injury, spinal cord, and peripheral nerve injury, cardiac infarction, cataracts, inflammation, restenosis, muscular dystrophy, and platelet aggregation. Pharmaceutical compositions, methods of using processes for preparing and novel intermediates useful in the processes are also disclosed.
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