- Keto/enol tautomerism in phenylpyruvic acids: Structure of the o- nitrophenylpyruvic acid
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The synthesis of a tautomeric keto/enol mixture of o-nitrophenylpyruvic acid followed the acid hydrolysis of the azlactone of o-nitrobenzaldehyde was carried out. The structures of the two tautomeric forms were assigned by NMR spectroscopy. X-ray diffraction of a single crystal revealed that the crystalline form corresponds to the keto tautomer. Quantum mechanics calculations in the gas phase confirmed the experimental findings in solution. (C) 2000 Elsevier Science B.V.
- Carpy,Haasbroek,Ouhabi,Oliver
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- A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders
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The eukaryotic translation initiation factor 4E (eIF4E) is the master regulator of cap-dependent protein synthesis. Overexpression of eIF4E is implicated in diseases such as cancer, where dysregulation of oncogenic protein translation is frequently observed. eIF4E has been an attractive target for cancer treatment. Here we report a high-resolution X-ray crystal structure of eIF4E in complex with a novel inhibitor (i4EG-BiP) that targets an internal binding site, in contrast to the previously described inhibitor, 4EGI-1, which binds to the surface. We demonstrate that i4EG-BiP is able to displace the scaffold protein eIF4G and inhibit the proliferation of cancer cells. We provide insights into how i4EG-BiP is able to inhibit cap-dependent translation by increasing the eIF4E-4E-BP1 interaction while diminishing the interaction of eIF4E with eIF4G. Leveraging structural details, we designed proteolysis targeted chimeras (PROTACs) derived from 4EGI-1 and i4EG-BiP and characterized these on biochemical and cellular levels. We were able to design PROTACs capable of binding eIF4E and successfully engaging Cereblon, which targets proteins for proteolysis. However, these initial PROTACs did not successfully stimulate degradation of eIF4E, possibly due to competitive effects from 4E-BP1 binding. Our results highlight challenges of targeted proteasomal degradation of eIF4E that must be addressed by future efforts.
- Fischer, Patrick D.,Papadopoulos, Evangelos,Dempersmier, Jon M.,Wang, Zi-Fu,Nowak, Rados?aw P.,Donovan, Katherine A.,Kalabathula, Joann,Gorgulla, Christoph,Junghanns, Pierre P.M.,Kabha, Eihab,Dimitrakakis, Nikolaos,Petrov, Ognyan I.,Mitsiades, Constantine,Ducho, Christian,Gelev, Vladimir,Fischer, Eric S.,Wagner, Gerhard,Arthanari, Haribabu
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supporting information
(2021/04/23)
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- A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction
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The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na2S2O4 in dioxane/water at reflux.
- Mamedov, Vakhid A.,Mamedova, Vera L.,Syakaev, Victor V.,Khikmatova, Gul'naz Z.,Korshin, Dmitry E.,Kushatov, Temur A.,Latypov, Shamil K.
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p. 3923 - 3925
(2018/10/02)
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- Synthesis of D- and L-Phenylalanine Derivatives by Phenylalanine Ammonia Lyases: A Multienzymatic Cascade Process
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The synthesis of substituted D-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). A simple high-throughput solid-phase screening method has also been developed to identify PALs with higher rates of formation of non-natural D-phenylalanines. The best variants were exploited in the chemoenzymatic cascade, thus increasing the yield and ee value of the D-configured product. Furthermore, the system was extended to the preparation of those L-phenylalanines which are obtained with a low ee value using PAL amination.
- Parmeggiani, Fabio,Lovelock, Sarah L.,Weise, Nicholas J.,Ahmed, Syed T.,Turner, Nicholas J.
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p. 4608 - 4611
(2015/04/14)
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- Deracemisation of aryl substituted α-hydroxy esters using Candida parapsilosis ATCC 7330: Effect of substrate structure and mechanism
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Candida parapsilosis ATCC 7330 was found to be an efficient biocatalyst for the deracemisation of aryl α-hydroxy esters (65-85% yield and 90-99% ee). A variety of aryl and aryl substituted α-hydroxy esters were synthesized to reflect steric and electronic effects on biocatalytic deracemisation. The mechanism of this biocatalytic deracemisation was found to be stereoinversion.
- Baskar,Pandian,Priya,Chadha, Anju
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p. 12296 - 12306
(2007/10/03)
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- Phenylpyruvic acid derivatives as enzyme inhibitors: Therapeutic potential on macrophage migration inhibitory factor
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Phenylpyruvic acid derivatives are obtained by hydrolysing aromatic Z/E azlactones. Keto tautomers interact with enzyme systems such as phenylalanine dehydrogenase or carboxypeptidase A whereas enol tautomers are potential inhibitors on the phenylpyruvate tautomerase activity catalysed by Macrophage Migration Inhibitory Factor (MIF). MIF being a key molecule in immune and inflammatory processes several structures with reasonable interaction with MIF and protocol for specific synthesis are presented. Birkhaeuser Boston 2004.
- Carpy, Alain J. M.,Haasbroek, Petrus P.,Oliver, Douglas W.
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p. 565 - 577
(2007/10/03)
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- Reactive dyeing systems using dyes with carboxylic acid groups on polyvinyl alcohol
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Carboxy substituted aromatic chromophores are reactively linked to fibers containing alcoholic hydroxyl groups, amino groups or thiol groups, such as cellulosic fibers, with the linkage produced in the presence of a cyanamide compound, such as cyanamide or dicyandiamide.
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- Reactive dyeing systems using dyes with carboxylic acid groups
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Carboxy substituted aromatic chromophores are reactively linked to fibers containing alcoholic hydroxyl groups, amino groups or thiol groups, such as cellulosic fibers, with the linkage produced in the presence of a cyanamide compound, such as cyanamide or dicyandiamide.
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