The structure of nagstatin, a new inhibitor of N-acetyl-.BETA.-D-glucosaminidase.

Aoyama, Takayuki; Naganawa, Hiroshi; Suda, Hiroyuki; Uotani, Kazumichi; Aoyagi, Takaaki; Takeuchi, Tomio

doi:10.7164/antibiotics.45.1557

Cited by 88 publications

(36 citation statements)

References 2 publications

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“…R f (hexane/AcOEt 11 : 9) 0. 24 Methyl 3-Cyano-3-deoxy-b-l-xylopyranoside (13) and Methyl 4-Cyano-4-deoxy-2,3-O-isopropylidene-a-dlyxopyranoside (15). A cooled soln.…”

Section: Experimental Partmentioning

confidence: 99%

Synthesis of Fusion‐Isomeric Imidazopyridines and Their Evaluation as Inhibitors of syn‐ and anti‐Protonating Glycosidases

Mohal

Vasella

2005

Helvetica Chimica Acta

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The galacto-and gluco-configured imidazopyridines 4 and 5 were synthesised as potential inhibitors of synprotonating b-glycosidases. Methyl a-d-lyxopyranoside (9) was transformed into the 3,4-anhydro-b-l-riboside 16, which, upon treatment with Et 2 AlCN, gave the nitrile 17 (76 ± 85%). Reaction of 17 with the dimethyl aluminate of aminoacetaldehyde dimethyl acetal led directly to the branched chain lyxo-configured imidazole 27 (53%) that was hydrolysed to an equilibrating mixture of 4 and 28 ± 30. Oxido reduction of 27 provided the arabino-configured imidazole 42 (ca. 48% from 27). Hydrolysis of 42 led to the mixture 5/45 (63 ± 90%). antiProtonating b-galactosidases and b-glucosidases (families 1 and 2) were only weakly inhibited by 4/28 ± 30 and 5/ 45, respectively. Also the syn-protonating cellulase (Cel7A) was weakly inhibited by the monosaccharide mimics 5/45, suggesting either that monosaccharide mimics are too small to inhibit Cel7A, or that fusion isomeric tetrahydroimidazo[1,2-a]pyridines are not a suitable scaffold for the inhibition of syn-protonating glycosidases.Introduction. ± Selective inhibitors of anti-and syn-protonating glycosidases [1] will be useful to specify the (relative) position of the catalytic acid; they also have the potential of being highly selective. Of particular interest are complementary inhibitors of syn-and anti-protonating glycosidases possessing a common scaffold, as this would facilitate a comparative interpretation of the inhibitory activity. However, there are as yet no inhibitors selective for syn-protonating (a-or b-) glycosidases.The anti-and syn-protonating glycosidases differ by the trajectory of the proton transfer from the catalytic acid AH to the glycosidic oxygen (I and II) and the tetrahydroimidazo[1,2-a]pyridines of type 1 are strong (about nanomolar) inhibitors of

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“…R f (hexane/AcOEt 11 : 9) 0. 24 Methyl 3-Cyano-3-deoxy-b-l-xylopyranoside (13) and Methyl 4-Cyano-4-deoxy-2,3-O-isopropylidene-a-dlyxopyranoside (15). A cooled soln.…”

Section: Experimental Partmentioning

confidence: 99%

Synthesis of Fusion‐Isomeric Imidazopyridines and Their Evaluation as Inhibitors of syn‐ and anti‐Protonating Glycosidases

Mohal

Vasella

2005

Helvetica Chimica Acta

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“…± Nagstatin (1), a N-acetylgalactosamine-derived tetrahydroimidazopyridine possessing a carboxymethyl substituent at C(2) [1] was isolated from the fermentation broth of Streptomyces amakusaensis in 1992 [2] and synthesized in 1995 by Tatsuta et al [3] [4]. It inhibits several glycosidases, most notably hog kidney Nacetyl-b-d-glucosaminidase (IC 50 4 nm) [2] [5].…”

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confidence: 99%

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

Terinek

Vasella

2004

Helvetica Chimica Acta

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The gluco-and manno-tetrahydropyridoimidazole-2-acetates and -acetic acids 16 and 17, and 20 and 21, respectively, were synthesized by condensation, in the presence of HgCl 2 , of the known thionolactam 26 with the b-amino ester 25 that was obtained by addition of AcOMe to the imine 22, followed by debenzylation. The resulting methyl esters 16 and 20 were hydrolyzed to the acetic acids 17 and 21. The (methoxycarbonyl)-imidazole 14 and the acid 15 were obtained via the known aldehyde 29. The imidazoles 14 ± 17, 20, and 21 were tested as inhibitors of the b-glucosidase from Caldocellum saccharolyticum, the a-glucosidase from brewers yeast, the b-mannosidase from snail, and the a-mannosidase from Jack beans (Tables 1 ± 3). There is a similar dependence of the K i values on the nature of the C(2)-substituent in the gluco-and manno-series. With the exception of 19, manno-imidazoles are weaker inhibitors than the gluco-analogues. The methyl acetates 16 and 20 are 3 ± 4 times weaker than the methyl propionates 5 and 11, in agreement with the hydrophobic effect. The gluco-configured (methoxycarbonyl)-imidazole 14 is 20 times weaker than the methyl acetate 16, reflecting the reduced basicity of 14, while the manno-configured (methoxycarbonyl)-imidazole 18 is only 1.2 times weaker than the methyl acetate 20, suggesting a binding interaction of the MeOCO group and the b-mannosidase. The carboxylic acids 6, 12, 15, 17, 19, and 21 are weaker inhibitors than the esters, with the propionic acids 6 and 12 being the strongest and the carboxy-imidazoles 15 and 19 the weakest inhibitors. The manno-acetate 21 inhibits the b-mannosidase ca. 8 times less strongly than the propionate 12, but only 1.5 times more strongly than the carboxylate 19, suggesting a compensating binding interaction also of the COOH group and the b-mannosidase. The a/b selectivity for the gluco-imidazoles ranges between 110 for 15 and 13.4´10 3 for 6; the manno-imidazoles are less selective. The methyl propionates proved the strongest inhibitors of the a-glucosidase (IC 50 (5) 25 mm) and the a-mannosidase (K i (11) 0.60 mm). . The carboxymethyl group at C(2) does not appear to be important for the inhibitory activity, since debranched nagstatin analogues and related C(2)-unsubstituted glucose-and mannose-derived tetrahydroimidazopyridines are also potent inhibitors of b-glycosidases [5 ± 7]. These observations and the rationalisation of the inhibitory activity of these and analogous azoles ± their similarity with the putative reaction intermediate, and the cooperative interaction of the azole ring with the catalytic acid and nucleophile ± indicated a negligible role for the substituents at C(2) [8 ± 10]. Subsequently, however, it was shown that C(2)-substituents of tetrahydropyridoimidazoles (and corresponding substituents of related azoles and pyrroles) can strongly affect the inhibitory properties, either indirectly, by competing with the catalytic acid for H-bonding to the glycosidic heteroatom, and/or

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“…PheGlcIm is a representative of the glucoimidazoles (GlcIm), which are excellent chemical tools for studying three-dimensional structures that mimic transition states. For example, PheGlcIm is a nagstatin-type mimic of the reactive intermediate that can be isolated from culture filtrates of Streptomyces amakusaensis (12), or prepared synthetically; nagstatin is an inhibitor of N-acetyl-␤-D-glucosaminidase (13). PheGlcIm has a trigonal anomeric center attached to an exocyclic N atom, which corresponds to the "glycosidic heteroatom," and an endocyclic N atom of the tetrahydropyridine moiety.…”

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confidence: 99%

Three-dimensional Structure of the Barley β-d-Glucan Glucohydrolase in Complex with a Transition State Mimic

Hrmová

Gori

Smith

et al. 2004

Journal of Biological Chemistry

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Glucophenylimidazole (PheGlcIm), a tetrahydroimidazopyridine-type inhibitor and 4 H 3 conformer mimic of a glucoside, binds very tightly to a barley ␤-D-glucan glucohydrolase, with a K i constant of 2 ؋ 10 ؊9 M and a ⌬G of 51 kJ mol ؊1 . PheGlcIm binds to the barley ␤-D-glucan glucohydrolase ϳ2 ؋ 10 5 times tighter than laminarin, which is the best non-synthetic ground-state substrate found so far for this enzyme, 10 6 times tighter than 4-nitrophenyl ␤-D-glucopyranoside, and 2 ؋ 10 7 tighter than glucose. The three-dimensional structure of the ␤-D-glucan glucohydrolase with bound PheGlcIm indicates that the complex resembles a hypothetical transition state during the hydrolytic cycle, that the enzyme derives substrate binding energy from the "aglycone" portion of the ligand, and that it also reveals an anti-protonation trajectory for hydrolysis. Continuous electron densities at the 1.6 level form between the three active site residues Asp 95 , His 207 , and Asp 285 , and the C6OH, C7OH, C8OH, and C9OH groups of PheGlcIm. These electron densities correspond to the most favorable interactions in the three-dimensional structure of the ␤-D-glucan glucohydrolase-PheGlcIm complex and indicate atomic distances equal to or less than 2.55 Å. The crystallographic data were corroborated with ab initio molecular orbital calculations. The data indicate that the 4 E conformation of the glucose part of PheGlcIm is critical for tight binding and provide the first evidence for probable substrate distortion during catalysis by this enzyme.

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The structure of nagstatin, a new inhibitor of N-acetyl-.BETA.-D-glucosaminidase.

Cited by 88 publications

References 2 publications

Synthesis of Fusion‐Isomeric Imidazopyridines and Their Evaluation as Inhibitors of syn‐ and anti‐Protonating Glycosidases

Synthesis of Fusion‐Isomeric Imidazopyridines and Their Evaluation as Inhibitors of syn‐ and anti‐Protonating Glycosidases

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

Three-dimensional Structure of the Barley β-d-Glucan Glucohydrolase in Complex with a Transition State Mimic

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