1.Pharmacological characterization of the novel γ-secretase modulator AS2715348, a potential therapy for Alzheimer's disease, in rodents and nonhuman primates.
Mitani Y1, Akashiba H2, Saita K2, Yarimizu J2, Uchino H2, Okabe M2, Asai M2, Yamasaki S3, Nozawa T4, Ishikawa N5, Shitaka Y2, Ni K2, Matsuoka N2. Neuropharmacology. 2014 Apr;79:412-9. doi: 10.1016/j.neuropharm.2013.12.013. Epub 2013 Dec 25.
γ-Secretase is the enzyme responsible for the intramembranous proteolysis of various substrates, such as amyloid precursor protein (APP) and Notch. Amyloid-β peptide 42 (Aβ42) is produced through the sequential proteolytic cleavage of APP by β- and γ-secretase and causes the synaptic dysfunction associated with memory impairment in Alzheimer's disease. Here, we identified a novel cyclohexylamine-derived γ-secretase modulator, {(1R*,2S*,3R*)-3-[(cyclohexylmethyl)(3,3-dimethylbutyl)amino]-2-[4-(trifluoromethyl)phenyl]cyclohexyl}acetic acid (AS2715348), that may inhibit this pathological response. AS2715348 was seen to reduce both cell-free and cellular production of Aβ42 without increasing levels of APP β-carboxyl terminal fragment or inhibiting Notch signaling. Additionally, the compound increased Aβ38 production, suggesting a shift of the cleavage site in APP. The inhibitory potency of AS2715348 on endogenous Aβ42 production was similar across human, mouse, and rat cells.
2.A pair of chiral fluorescent sensors for enantioselective recognition of mandelate in water.
Xu KX1, Kong HJ, Zu FL, Yang L, Wang CJ. Spectrochim Acta A Mol Biomol Spectrosc. 2014 Jan 24;118:811-5. doi: 10.1016/j.saa.2013.09.083. Epub 2013 Oct 8.
A pair of chiral compounds S-1 and R-1 derived from (1S, 2S) or (1R, 2R)-1, 2-diphenylethane-1, 2-diamine were designed and synthesized, the interactions of S-1 and R-1 with mandelate were studied in H2O (0.01 M HEPES buffer, pH=7.4) by fluorescence titration experiments. The sensors S-1 and R-1 were found to present enantioselective fluorescent sensing ability to mandelate. The results indicated that the sensors S-1 and R-1 were very promising to be used as fluorescent sensors in determining the enantiomeric composition of mandelate in H2O.
3.Chiral Recognition Studies of α-(Nonafluoro-tert-butoxy)carboxylic Acids by NMR Spectroscopy.
Nemes A1, Csóka T1, Béni S2,3, Farkas V4, Rábai J1, Szabó D1. J Org Chem. 2015 Jun 19;80(12):6267-74. doi: 10.1021/acs.joc.5b00706. Epub 2015 Jun 10.
Three chiral α-(nonafluoro-tert-butoxy)carboxylic acids (R)-1, (RS)-2, (R)-3 were synthesized to examine their application as chiral solvating agents with amines. As a model compound, first (S)- and/or (RS)-α-phenylethylamine was used, and their diastereomeric salts were investigated by (1)H and (19)F NMR and ECD spectroscopy. The NMR spectroscopic studies were carried out at room temperature using the slightly polar CDCl3 and apolar C6D6 as solvents in 5 mM and 54 mM concentrations. The difference of the chemical shifts (Δδ) in the diastereomeric complexes is comparable with other, well-known chiral derivatizing and solvating agents (e.g., Mosher's acid, Pirkle's alcohol). Diastereomeric salts of racemic acids (RS)-1 and (RS)-2 with biologically active amines (1R,2S)-ephedrine and (S)-dapoxetine were also investigated by (19)F NMR spectroscopy.
4.Exploiting aromatic interactions for β-peptide foldamer helix stabilization: a significant design element.
Mándity IM1, Monsignori A, Fülöp L, Forró E, Fülöp F. Chemistry. 2014 Apr 14;20(16):4591-7. doi: 10.1002/chem.201304448. Epub 2014 Mar 24.
Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side-chains in β-peptide oligomers by intramolecular backbone-side chain CH-π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self-assembly in a polar medium for the β-peptide H10/12 helices. NMR, ECD, and molecular modeling results indicated that the oligomers formed by cis-[1S,2S]- or cis-[1R,2R]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (ATENAC) and cis-[1R,2S]- or cis-[1S,2R]-2-aminocyclohex-3-enecarboxylic acid (ACHEC) residues promote stable H10/12 helix formation with an alternating backbone configuration even at the tetrameric chain length. These results support the view that aromatic side-chains can be applied for helical structure stabilization. Importantly, this is the first observation of a stable H10/12 helix with tetrameric chain-length. The hydrophobically driven self-assembly was achieved for the helix-forming oligomers, seen as vesicles in transmission electron microscopy images.
