- Tautomeric modification of GIcNAc-thiazoline
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The potent OGIcNAcase (OGA) inhibitor GIcNAc-thiazoline has been modified by buffer- or acylation-induced imine-to-enamine conversion and then electrophile or radical addition (Xn = D3, F, N 3, OH, SMe, COCF3, CF3). Several functionalized GIcNAc-thiazolines show highly selective inhibition of OGA vs human hexosaminidase and thus have promise as tools for targeted investigations of OGA, an enzyme linked to diabetes and neurodegeneration. A new radical addition/fragmentation reaction of the N-(trifluoroacetyl)enamine has been discovered.
- Knapp, Spencer,Abdo, Mohannad,Ajayi, Kehinde,Huhn, Richard A.,Emge, Thomas J.,Kim, Eun Ju,Hanover, John A.
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- Combining weak affinity chromatography, NMR spectroscopy and molecular simulations in carbohydrate-lysozyme interaction studies
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By examining the interactions between the protein hen egg-white lysozyme (HEWL) and commercially available and chemically synthesized carbohydrate ligands using a combination of weak affinity chromatography (WAC), NMR spectroscopy and molecular simulations, we report on new affinity data as well as a detailed binding model for the HEWL protein. The equilibrium dissociation constants of the ligands were obtained by WAC but also by NMR spectroscopy, which agreed well. The structures of two HEWL-disaccharide complexes in solution were deduced by NMR spectroscopy using 1H saturation transfer difference (STD) effects and transferred 1H,1H-NOESY experiments, relaxation-matrix calculations, molecular docking and molecular dynamics simulations. In solution the two disaccharides β-d-Galp-(1→4) -β-d-GlcpNAc-OMe and β-d-GlcpNAc-(1→4)-β-d-GlcpNAc-OMe bind to the B and C sites of HEWL in a syn-conformation at the glycosidic linkage between the two sugar residues. Intermolecular hydrogen bonding and CH/π-interactions form the basis of the protein-ligand complexes in a way characteristic of carbohydrate-protein interactions. Molecular dynamics simulations with explicit water molecules of both the apo-form of the protein and a ligand-protein complex showed structural change compared to a crystal structure of the protein. The flexibility of HEWL as indicated by a residue-based root-mean-square deviation analysis indicated similarities overall, with some residue specific differences, inter alia, for Arg61 that is situated prior to a flexible loop. The Arg61 flexibility was notably larger in the ligand-complexed form of HEWL. N,N′-Diacetylchitobiose has previously been observed to bind to HEWL at the B and C sites in water solution based on 1H NMR chemical shift changes in the protein whereas the disaccharide binds at either the B and C sites or the C and D sites in different crystal complexes. The present study thus highlights that protein-ligand complexes may vary notably between the solution and solid states, underscoring the importance of targeting the pertinent binding site(s) for inhibition of protein activity and the advantages of combining different techniques in a screening process. The Royal Society of Chemistry 2012.
- Landstroem, Jens,Bergstroem, Maria,Hamark, Christoffer,Ohlson, Sten,Widmalm, Goeran
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supporting information; scheme or table
p. 3019 - 3032
(2012/05/07)
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- Solid-phase synthesis of Di-N-Acetyl-β-chitobiosyl NAG-thiazoline
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The solid-phase synthesis of di-N-acetyl-β-chitobiosyl NAG (N-acetyl D-glucosamine)-thiazoline 3 was reported. After the 6-O-benzyl NAG-thiazoline 9, NHCbz trichloroacetimidate donors 14, and 21 were synthesized, and solid-phase synthesis was performed using the Wang resin as support. The target di-N-acetyl-β-chitobiosyl NAGthiazoline 3 was obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively. donors, Wang resin, Glycosylation reactions.
- Huang, Gangliang,Chen, Ya
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scheme or table
p. 649 - 651
(2012/05/20)
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- SELECTIVE GLYCOSIDASE INHIBITORS, METHODS OF MAKING INHIBITORS, AND USES THEREOF
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The invention comprises compounds for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions containing the compounds or prodrugs of the compounds. The invention also comprises animal models and methods of making the animal models for studying diseases and disorders related to deficiency or overexpression of O-GIcNAcase, accumulation or deficiency of O-GIcNAc, and treatment of such diseases and disorders. The invention also comprises methods of treating such diseases and disorders. The invention also comprises methods of making the compounds, and methods of making selective glycosidase inhibitors
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Page/Page column 36; 40-41
(2010/11/23)
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- Iminocyclitol inhibitors of hexoaminidase and glycosidase
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Designed iminocylitols that have potent inhibition activity with respect to hexominidases and glycosides are disclosed.
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Page/Page column 20; sheet 17
(2010/02/08)
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- Synthesis of N-acetylglucosamine thiazoline/lipid II hybrids
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Potential inhibitors of transglycosylases involved in bacterial cell wall biosynthesis were synthesized by combining N-acetylglucosamine thiazoline, a potent inhibitor of β-hexosaminidase, with functional groups present in lipid II, the natural substrate of the transglycosylases.
- Ritter, Thomas K.,Wong, Chi-Huey
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p. 615 - 618
(2007/10/03)
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