- β-Indolyloxy Functionalized Aspartate Analogs as Inhibitors of the Excitatory Amino Acid Transporters (EAATs)
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The excitatory amino acid transporters (EAATs) mediate uptake of the major excitatory neurotransmitter l-glutamate (Glu). The essential functions governed by these transporters in regulating the central Glu level make them interesting therapeutic targets in a wide range of neurodegenerative and psychiatric disorders. l-Aspartate (Asp), another EAAT substrate, has served as a privileged scaffold for the development of EAAT inhibitors. In this study, we designed and synthesized the first β-indolyloxy Asp analogs 15a-d with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of 15a-d were characterized at hEAAT1-3 and rEAAT4 in a conventional [3H]-d-Asp uptake assay. Notably, thiophene analog 15b and the para-Trifluoromethyl phenyl analog 15d were found to be hEAAT1,2-preferring inhibitors exhibiting IC50values in the high nanomolar range (0.21-0.71 μM) at these two transporters versus IC50values in the low micromolar range at EAAT3,4 (1.6-8.9 μM). In summary, the results presented herein open up for further structure-Activity relationship studies of this new scaffold.
- Liu, Na,Jensen, Anders A.,Bunch, Lennart
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supporting information
p. 2212 - 2220
(2020/10/05)
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- Synthesis of a protected derivative of (2R,3R)-β-hydroxyaspartic acid suitable for Fmoc-based solid phase synthesis
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Synthesis of d-threo-hydroxyaspartic acid, orthogonally protected and compatible with an Fmoc solid-phase peptide synthesis strategy is reported. This synthetic procedure starting from (2R,3R)-dimethyltartrate is adaptable to a multi-gram scale. 2,2-Dimethyl-5-oxo-1,3-dioxazolane formation between the β-hydroxy alcohol and the β-carboxylic functions constitutes a key step of the differentiation of the two acidic functions allowing the preparation of (2R,3R)-Fmoc-β-hydroxyaspartic α-allyl ester.
- France, Boyaud,Bruno, Viguier,Nicolas, Inguimbert
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p. 158 - 161
(2013/02/22)
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- Effect of electron-withdrawing substituents on the epoxide ring: An experimental and theoretical electron density analysis of a series of epoxide derivatives
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A series of acceptor-substituted epoxide derivatives is scrutinized by means of experimental and theoretical electron-density investigations. Due to the possibility of nucleophilic ring-opening, the epoxide ring is not only a very useful functional group in organic synthesis, but acceptor-substituted epoxides are valuable building blocks for the design of protease inhibitors. Therefore, the electron-density analysis in this work focuses on two main aspects that can contribute to rational drug design: (i) the quantification of the electron-withdrawing substituent effects on the epoxide ring and (ii) the intermolecular interactions involving the epoxide ring in combination with different substituents. It can be shown that the electron-withdrawing properties of the substituents cause an elongation of the C-C bonds in the epoxide rings and the loss of electron density can be measured by an analysis of critical points, atomic charges, and the source function. The different strengths of the substituents are reflected in these properties. Covalent and electrostatic contributions to the intermolecular interactions and thus the lattice energies are depicted on different molecular surfaces.(Figure Presented)
- Grabowsky, Simon,Schirmeister, Tanja,Paulmann, Carsten,Pfeuffer, Thomas,Luger, Peter
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experimental part
p. 1305 - 1318
(2011/04/23)
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- Process for the production of pentostatin aglycone and pentostatin
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A novel, scaleable and improved process for preparing pentostatin and its analogs is disclosed. The method comprises the diastereospecific synthesis of the nucleobase from commercially available L-Dialkyl tartarates.
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- A revised mechanism for chemoselective reduction of esters with borane-dimethyl sulfide complex and catalytic sodium tetrahydroborate directed by adjacent hydroxyl group
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The plausible mechanism for the reduction of the ester groups with a strong preference for one located α to the hydroxyl groups of (S)-malates and (R,R)-tartrate-based derivatives has been proposed together with some results with regard to its applications to the syntheses of chiral synthons.
- Saito,Ishikawa,Kuroda,Koga,Moriwake
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p. 4067 - 4086
(2007/10/02)
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- NOVEL APPROACH TO STEREOISOMERICALLY FULL SET OF OPTICALLY PURE 2,3-EPOXYESTERS FROM TARTARIC ACIDS
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Four possible stereoisomers of 4-(t-butyldimethylsilyloxy)-2,3-epoxybutanoic acid esters have been synthesized highly efficiently in both diastereomerically and enantiomericaly pure state from tartaric acids.
- Saito, Seiki,Nagao, Yuki,Miyazaki, Masahiro,Inaba, Masami,Moriwake, Toshio
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p. 5249 - 5252
(2007/10/02)
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