2000
DOI: 10.1021/ja993805j
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Nanomolar versus Millimolar Inhibition by Xylobiose-Derived Azasugars:  Significant Differences between Two Structurally Distinct Xylanases

Abstract: The synthesis of xylobiose-derived nitrogen-containing inhibitors of xylanase is described starting with accessible precursors through efficient synthetic schemes. Four disaccharides were identified as powerful competitive inhibitors of the retaining family 10 xylanase, Cex, from Cellulomonas fimi, namely imidazole (K i ) 150 nM), lactam oxime (K i ) 370 nM), isofagomine (K i ) 130 nM), and deoxynojirimycin (K i ) 5800 nM) derivatives of xylobiose. By contrast, none of the compounds inhibited the family 11 xyl… Show more

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Cited by 62 publications
(67 citation statements)
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References 51 publications
(114 reference statements)
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“…4 In this sense, optically pure 3,4-dihydroxypiperidine is an interesting structure since the (3R,4R)-trans isomer is an inhibitor of -D-glucoronidase 5 and has been used as intermediate for the preparation of a xylanase inhibitor (Figure 1). 6 Also, this structure is a suitable precursor of the gastroprokinetic agent cisapride. 7 On the other hand, the cis-isomer is an intermediate for the preparation of the antidepressant ifoxetine.…”
Section: Introductionmentioning
confidence: 99%
“…4 In this sense, optically pure 3,4-dihydroxypiperidine is an interesting structure since the (3R,4R)-trans isomer is an inhibitor of -D-glucoronidase 5 and has been used as intermediate for the preparation of a xylanase inhibitor (Figure 1). 6 Also, this structure is a suitable precursor of the gastroprokinetic agent cisapride. 7 On the other hand, the cis-isomer is an intermediate for the preparation of the antidepressant ifoxetine.…”
Section: Introductionmentioning
confidence: 99%
“…Cex is a family 10 glycosyl hydrolase, found in the microorganism Cellulomonas fimi. It catalyzes the hydrolytic cleavage of ␤-1,4-linked polymers of xylose [18]. Five high-affinity xylobiose-derived aza-sugars that inhibit the catalytic activity of Cex have been described: imidazole, lactam oxime, deoxynojirimycin, isofagomine lactam, and isofagomine [19].…”
mentioning
confidence: 99%
“…Figure 1 shows the structures of the three inhibitors used here, with binding affinity increasing in the order xylobiosyl-deoxynojirimycin (X 2 DNJ), xylobiosyl-isofagomine lactam (X 2 IL), and xylobiosyl-isofagomine (X 2 IF). All inhibitors consist of two sugars: a common distal xylose which binds to the Ϫ2 sub-site of Cex, and a distinct proximal aza-sugar which binds to the Ϫ1 sub-site [18,20]. Cex binds to the proximal and distal sugars through van der Waals interactions, electrostatic interactions, and a series of hydrogen bonds to amino acid side chains.…”
mentioning
confidence: 99%
“…Cex (from the micro-organism Cellulomonas fimi) is a family 10 glycosal hydrolase. The catalytic domain of Cex folds as a (α/β) 8 -barrel, and catalyses hydrolytic cleavage of β-1,4 linked polymers of D-xylose [27]. A series of small-molecule inhibitors that noncovalently bind at the active site of the catalytic domain of Cex (Cex-cd) with high affinity have been described [27]: imidazole, lactam oxime, deoxynojirimycin (X 2 DNJ), isofagomine lactam (X 2 IL), and isofagomine (X 2 IF), three of which are used in this work and are shown in Figure 1.…”
Section: Introductionmentioning
confidence: 99%
“…The catalytic domain of Cex folds as a (α/β) 8 -barrel, and catalyses hydrolytic cleavage of β-1,4 linked polymers of D-xylose [27]. A series of small-molecule inhibitors that noncovalently bind at the active site of the catalytic domain of Cex (Cex-cd) with high affinity have been described [27]: imidazole, lactam oxime, deoxynojirimycin (X 2 DNJ), isofagomine lactam (X 2 IL), and isofagomine (X 2 IF), three of which are used in this work and are shown in Figure 1. These xylobiose-derived nitrogen-containing inhibitors consist of two sugars, a common distal xylose that binds to the −2 sub-site of Cex and a distinct proximal aza-sugar that binds to the −1 sub-site [27,28].…”
Section: Introductionmentioning
confidence: 99%