Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases.

Terinek, Miroslav; Vasella, Andrea

doi:10.1002/chin.200518111

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“…The phenyl glucoimidazole (PheGlcIm) and anilinomethyl glucoimidazole (AmGlcIm) used in this work are excellent chemical tools for mimicking transition states of glycoside hydrolases (5)(6)(7)(8). These inhibitors belong to the C2substituted gluco-configured tetrahydroimidazopyridine fam- ily of inhibitors that possess a nonhydrolyzable glycosidic C-N bond between C10 and N1 of the "sugar" and imidazole moieties, and their anomeric carbons are sp 2 hybridized and double-bonded with the exocyclic N1 atoms (9,10). The conformation of these inhibitors is analogous to those of gluconojiritetrazoles, which in the solid state or in D 2 O adopt a 4 H 3 conformation that is similar to an envelope ( 4 E) (6,11).…”

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Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley^,

et al. 2005

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The interactions of a transition state mimic anilinomethyl glucoimidazole (AmGlcIm), with a K(i) constant of 0.6 x 10(-)(9) M and a Gibbs free energy value of -53.5 kJ/mol, with a family GH3 beta-d-glucan glucohydrolase from barley have been analyzed crystallographically and by ab initio quantum mechanical modeling. AmGlcIm binds 3 times more tightly to the beta-d-glucan glucohydrolase than a previously investigated phenyl glucoimidazole. In the enzyme-AmGlcIm complex, an additional residue, Tyr253, and a water molecule positioned between subsites -1 and +1 are recruited for binding. Analyses of the two binary complexes reveal the following. (i) An intricate network exists in which hydrogen bonds between the enzyme's catalytic pocket residues Lys206, His207, Tyr253, Asp285, and Glu491 and the glucoimidazoles are shorter by 0.15-0.53 A, compared with distances of hydrogen bonds in the Michaelis complex. (ii) The "glucose" moiety of the glucoimidazoles adopts a (4)E conformation that is vital for the low-nanomolar binding. (iii) The N1 atoms of the glucoimidazoles are positioned nearly optimally for in-line protonation by the Oepsilon1 atom of the catalytic acid/base Glu491. (iv) The enzyme derives binding energies from both glycone and aglycone components of the glucoimidazoles. (iv) The prevalent libration motion of the two domains of the enzyme could play a significant role during induced fit closure in the active site. (v) Modeling based on the structural data predicts that protons could be positioned on the N1 atoms of the glucoimidazoles, and the catalytic acid/base Glu491 could carry an overall negative charge. (vi) The enzyme-AmGlcIm complex reveals the likely structure of an early transition state during hydrolysis. Finally, the high-resolution structures enabled us to define minimal structures of oligosaccharides attached to Asn221, Asn498, and Asn600 N-glycosylation sites.

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Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley^,

et al. 2005

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“…1 was treated with various Grignard reagents to give racemic N-benzyl protected aminoacetals, rac-2a-e (Enders et al 1993;Quelet and Chastrette 1959;Chastrette 1962;Kido and Watanabe 1987). Hydrogenolysis of rac-2a-e with palladium on carbon in methanol, afforded the expected racemic a-aminoacetals, rac-3a-e (Muralidharan et al 1994;Bringmann and Geisler 1989;Terinek and Vasella 2004b;Urban and Noe 2003;Winkler et al 2004). The combined yields in isolated rac-3a-e from DME after the three chemical steps reported in Scheme 3 and a final purification step by distillation were ranging between 25 and 45% (Albalat et al 2010).…”

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Resolution and absolute configuration of some α-aminoacetals: en route to enantiopure N-protected α-aminoaldehydes

Albalat¹,

Primazot²,

Wilhelm³

et al. 2011

Amino Acids

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The first successful resolution of rac-α-aminoacetals via diastereoisomeric salt formation with optically pure N-protected aminoacids is reported. The absolute configuration assignment of α-aminoacetal enantiomers is performed by an entirely non-racemizing chemical correlation method involving N-protection and a new efficient hydrolysis step followed by a reduction of the resulting N-protected α-aminoaldehyde intermediates. A racemization method of optically enriched α-aminoacetals is exemplified to allow valorisation of both enantiomers.

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Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases.

Cited by 2 publications

References 1 publication

Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley^,

Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley^,

Resolution and absolute configuration of some α-aminoacetals: en route to enantiopure N-protected α-aminoaldehydes

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Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases.

Cited by 2 publications

References 1 publication

Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley,

Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley,

Resolution and absolute configuration of some α-aminoacetals: en route to enantiopure N-protected α-aminoaldehydes

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Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley^,

Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d-Glucan Glucohydrolase from Barley^,