Synthesis and evaluation of two mannosamine-derived lactone-type inhibitors of snail β-mannosidase

Terinek, Miroslav; Vasella, Andrea

doi:10.1016/j.tetasy.2004.11.068

Cited by 20 publications

(15 citation statements)

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“…The mannosidase inhibitor ManI has been highlighted as a uniquely informative molecular probe that can be used to report on transition-state conformation for a variety of -mannosidase families (Zhu et al, 2010;Thompson et al, 2012;Williams et al, 2014;Tankrathok et al, 2015). ManI is derived by the annulation of a deoxymannojirimycin piperidine ring with an imidazole, resulting in double-bond character between C1 and the endocyclic N atom (Terinek & Vasella, 2005), thus providing shape mimicry of the oxocarbenium ion-like character present at the TS ‡ of glycosidasecatalysed hydrolysis. In particular, this compound has low energetic barriers between various boat and half-chair conformations, equivalent to catalytically relevant oxocarbenium ion conformations, meaning that the observed conformation of the inhibitor 'onenzyme' are those imposed by the enzyme, rather than from an intrinsic bias of the inhibitor (Williams et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Bacteroides thetaiotaomicron generates diverse α-mannosidase activities through subtle evolution of a distal substrate-binding motif

Thompson

Spears

Zhu

et al. 2018

Acta Cryst Sect D Struct Biol

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Section: Resultsmentioning

confidence: 99%

Bacteroides thetaiotaomicron generates diverse α-mannosidase activities through subtle evolution of a distal substrate-binding motif

Thompson

Spears

Zhu

et al. 2018

Acta Cryst Sect D Struct Biol

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“…The intercept of the x axis of a plot of k cat / K m against inhibitor concentration revealed the K i value. Mannoimidazole 28 and “thio α-1,2 mannobioside” 23 were synthesized as described previously. Swainsonine and kifunensine were purchased from Oxford Glycosystems.…”

Section: Methodsmentioning

confidence: 99%

Mechanistic insights into a Ca2+-dependent family of α-mannosidases in a human gut symbiont

et al. 2009

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Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are α-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state 4C1 chair conformation toward the transition state.

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“…s, exchange with CD 3 OD, NH 2 ); 3.62 (br. s, CH 2 ÀC (2) Table 4; additionally, 34.38 (t, CH 2 ÀC (2) 3089w, 3066w, 3019m, 3009m, 2954m, 2929m, 2869m, 1951w, 1875w, 1810w, 1736s, 1669s, 1603w, 1497s, 1455s, 1438m, 1408w, 1368m, 1268m, 1153m, 1097s, 1028m, (14). a) A mixture of 25 (142 mg, 0.250 mmol) and 10% Pd/C (140 mg) in AcOH (6 ml) was hydrogenated for 22 h at 6 bar and filtered over Celite (washing with 40 ml MeOH).…”

Section: Experimental Partmentioning

confidence: 99%

“…± We planned to synthesize the gluco-analogue 15 of nagstatin (1) via the gluco-and manno-configured hydroxy-imidazoles 22 and 23. These imidazoles should be obtained by condensing the selectively protected thionolactams 17 [14] or 18 [15] with the b-amino ester 19 [9], followed by selective deprotection of the products. The resulting alcohols 22 and 23 should be transformed into 15 by a Mitsunobu substitution, similarly as described for the galacto-and talo-analogues in the synthesis of nagstatin [3] [4] (Scheme 1).…”

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confidence: 99%

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

Terinek¹,

Vasella²

2005

Helvetica Chimica Acta

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The gluco-configured analogue 15 of nagstatin (1) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the b-amino ester 19. The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23; these alcohols were directly obtained by condensing 18 and 19. The attempted substitution of the C(8)ÀOH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated a-azido esters 24. The desired azide 25 was obtained by treating the manno-configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15. The imidazole-2-acetates 14 and 15 are nanomolar inhibitors of the Nacetyl-b-glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the b-glucosidase from Caldocellum saccharolyticum, and rather weak inhibitors of the snail b-mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their glucoconfiguration, both imidazopyridines 14 and 15 are stronger inhibitors of the b-N-acetylglucosaminidase from bovine kidney than nagstatin.Introduction. ± Nagstatin (1), a strong inhibitor of several hexosaminidases [1 ± 4], is a N-acetylgalactosamine-derived tetrahydropyridoimidazole-2-acetic acid [5]. Its inhibitory activity is essentially associated with the imidazole ring and not with the carboxymethyl substituent [2], although substituents on the imidazole ring may strongly affect the inhibition of b (and a-)-glycosidases [6 ± 8]. In the preceding paper [9], we described the influence of the hydrophobic character of C(2)-methyl ester and carboxylic acid substituents on the inhibition of b-glycosidases. Imidazole-2-propionates 10 ± 13 are stronger inhibitors of the b-glucosidase from Caldocellum saccharolyticum and of the b-mannosidase from snail than imidazole-2-acetates 6 ± 9, and these are stronger than imidazole-2-carboxylates 2 ± 5. There is a parallel sequence of inhibitory activity for the methyl esters and the corresponding acids, with the esters being stronger inhibitors.

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Synthesis and evaluation of two mannosamine-derived lactone-type inhibitors of snail β-mannosidase

Cited by 20 publications

References 59 publications

Bacteroides thetaiotaomicron generates diverse α-mannosidase activities through subtle evolution of a distal substrate-binding motif

Bacteroides thetaiotaomicron generates diverse α-mannosidase activities through subtle evolution of a distal substrate-binding motif

Mechanistic insights into a Ca2+-dependent family of α-mannosidases in a human gut symbiont

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

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