- Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95
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Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by 1H,15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.
- Zang, Jie,Ye, Fei,Solbak, Sara M. ?.,H?j, Lars J.,Zhang, Mingjie,Bach, Anders
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supporting information
p. 949 - 954
(2020/12/31)
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- Design, synthesis and antimalarial evaluation of novel thiazole derivatives
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As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.
- Bueno, José María,Carda, Miguel,Crespo, Benigno,Cu?at, Ana Carmen,de Cozar, Cristina,León, María Luisa,Marco, J. Alberto,Roda, Nuria,Sanz-Cervera, Juan F.
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supporting information
p. 3938 - 3944
(2016/08/01)
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- METHOD FOR PREPARING DI-ORGANO-DIALKOXYSILANES
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The present invention relates to a method for preparing di-organo-dialkoxysilanes, in particular di-organo-dialkoxysilanes wherein one or both of the organic substituents are bulky. The method comprises reacting a tetraalkoxysilane compound with a first Grignard reagent to form a mono-organo-tri-alkoxysilane compound, which is then reacted with a chlorinating agent to form a chlorinated mono-organo-di-alkoxysilane which is then reacted with a second Grignard reagent to form the di-organo-di-alkoxysilane compound.
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Paragraph 0056
(2013/07/19)
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- An ESR and HPLC-EC assay for the detection of alkyl radicals
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The correlation of lipid peroxidation with release of alkanes (RH) is considered a noninvasive method for the in vivo evaluation of oxidative stress. The formation of RH is believed to reflect a lipid hydroperoxide (LOOH)-dependent generation of alkoxyl radicals (LO·) that undergo β-scission with release of alkyl radicals (R·). Alternatively, R· could be spin-trapped with a nitrone before the formation of RH and analyzed by ESR. Extracts from the liver and lung of CCl4- and asbestos-treated rats that were previously loaded with nitrones exhibited ESR spectra suggesting the formation of iso-propyl, n-butyl, ethyl, and pentyl radical-derived nitroxides. In biological systems, various nitroxides with indistinguishable ESR spectra could be formed. Hence, experiments with N-tert-butyl-α-phenylnitrone (PBN) for spin trapping of R· were carried out in which the nitroxides formed were separated and analyzed by HPLC with electrochemical detection (EC). The C1-5 homologous series of PBN nitroxides and hydroxylamines were synthesized, characterized by ESR, GC-MS, and HPLC-EC, and used as HPLC standards. For in vivo generation and spin trapping of R·, rats were loaded with CCl4 and PBN. The HPLC-EC chromatograms of liver extracts from CCl4-treated rats demonstrated the formation of both the nitroxide and hydroxylamine forms of PBN/·CCl3, as well as the formation of a series of unidentified PBN nitroxides and hydroxylamines. However, formation of PBN adducts with retention times similar to these of the PBN/C2-5 derivatives was not observed. In conclusion, we could not correlate the production of PBN-detectable alkyl radicals with the reported CCl4-dependent production of C1-5 alkanes. We speculate that the major reason for this is the low steady-state concentrations of R· produced because only a small fraction of LO· undergo β-scission to release R·.
- Novakov,Feierman,Cederbaum,Stoyanovsky
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p. 1239 - 1246
(2007/10/03)
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- Perfumes comprising 3-alkylcycloalkanols
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Perfumes and perfumed products comprising 3-alkylcycloalkan-1-ols of formula (I), wherein R1represents hydrogen or a methyl, ethyl or propyl group; R2, R4and R5independently represent hydrogen or a methyl group; R3represents a saturated hydrocarbon group with 4-8 carbon atoms, provided that the first carbon atom of this hydrocarbon group is not a tertiary carbon atom, and n represents the numbers 1, 2 and 3. The invention also concerns compounds of formula (I) wherein R1represents a methyl, ethyl or propyl group and R2-R5are as outlined above.
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- Substituted thiophene derivative and plant disease control agent comprising the same as active ingredient
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A novel substituted thiophene derivatives represented by the formula (1) in the invention: STR1 wherein R is a straight or branched alkyl group having 3-12 carbon atoms, straight or branched halogenoalkyl group having 3-12 carbon atoms, straight or branched alkenyl group having 3-10 carbon atoms, straight or branched halogenoalkenyl group having 3-10 carbon atoms, or cycloalkyl group having 3-10 carbon atoms, the cycloalkyl group being unsubstituted or substituted with an alkyl group having 1-4 carbon atoms, R and --NHCOAr are adjacent to each other, and Ar is a heterocyclic group; have excellent control activity on various plant disease such as Gray mold, Powdery mildew, Blast and Rust, and are useful as a plant disease control agent due to outstanding residual effect on Botrytis cinerea and excellent effect on Gibberella zeae.
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- Substituted thiophene derivative and agricultural and horticultural fungicide containing the same as active ingredient
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The substituted thiophene derivative of the invention which is represented by the general formula (1) has a broad disease spectrum for a pathogenic fungus of various crops, exhibits an excellent controlling effect on disease such as gray mold, powdery mil
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- New Histidyl amino acid derivatives, and pharmaceutical composition comprising the same
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A compound of the formula: STR1 wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula: STR2 in which R5 is hydrogen or acyl and R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R2 is hydrogen or lower alkyl; or R1 and R2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower )alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; R3 is hydrogen or lower alkyl; and R4 is lower alkyl; and its pharmaceutically acceptable salt, processes for the preparation thereof and pharmaceutical composition comprising the same.
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- A NMR Study of the Dynamics of the Schlenk Equilibrium of 2-Methylpropylmagnesium Bromide in Tetrahydrofuran
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A 90 MHz proton NMR determination of the activation and thermodynamic parameters of the Schlenk equilibrium of 2-methylpropylmagnesium bromide in tetrahydrofuran is reported.The entropy of activation is consistent with bimolecular reactions of unassociated species proceeding through a transition state resembling a mixed-bridge dimer.The quantitative data confirm accepted concepts of the solvation states of the species involved. - Association equilibria were explored in order to ensure that they were insignificant under the conditions of the kinetic measurements on the Schlenk equilibria. - The association of di-2-methylpropylmagnesium is strongly concentration-dependent but almost temperature-independent.The exchange rate is too slow to be measured by NMR methods and much slower than the Schlenk equilibrium.The associates are either cyclic or cluster compounds, or, if linear, have an average degree of polymerization of 10. - The field positions of the resonances of RMgBr and R2Mg reverse at low temperature.
- Allen, Peter E. M.,Hagias, Stan,Lincoln, Stephen F.,Mair, Clyde,Williams, Evan H.
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p. 515 - 519
(2007/10/02)
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- Thermochemical Bond Dissociation Energies of Carbon-Magnesium Bonds
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The heats of formation of 29 alkylmagnesium bromides, isobutyl bromide, and neopentyl bromide have been determined, and bond dissociation energies have been derived for the Grignard reagents.For saturated alkyl derivatives the C-Mg bond strength decreases with an increasing number of β-hydrogens in the series methyl, neopentyl, isobutyl, butyl, ethyl, 1-ethylpropyl, 1-methylpropyl, isopropyl, and t-butyl.Bonding in alkyl bromides and alkylmagnesium bromides is discussed.
- Holm, Torkil
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p. 464 - 467
(2007/10/02)
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