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

Abstract

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.

Small Molecule Inhibitors of a Glycoside Hydrolase Attenuate Inducible AmpC-mediated β-Lactam Resistance

“…These two human enzymes are functionally related to NagZ, since they also cleave GlcNAc off from the nonreducing termini of glycoconjugates, but they use a different catalytic mechanism and are of unrelated sequence (62). Little is known about the inhibitory susceptibility of NagZ to these various inhibitors, but we expected, however, that at least one of PUGNAc 1, LOGNAc, or gluco-nagstatin should be a potent inhibitor of NagZ, since the glucose analogues have been shown to effectively inhibit mechanistically related ␤-glucosidases from other families of glycoside hydrolases (51,58).…”

“…All three compounds were found to be good inhibitors (Table 1), but LOGNAc was less potent than PUGNAc, and, surprisingly, gluco-nagstatin is still less potent although it is highly effective against ␤-N-acetylglucosaminidases from CAZy family 20 of glycoside hydrolases (58). These findings focused our efforts on PUGNAc 1, which unfortunately is also a potent inhibitor of the human family 84 O-GlcNAcase (55,63) and family 20 lysosomal ␤-hexosaminidases (52,57).…”

2-Acetamido-N-benzyl-1,4-imino-1,2,4-trideoxy-L-arabinitol 0.33-hydrate

“…Monosaccharides in which the ring oxygen has been replaced by nitrogen constitute a general class of glycosidase inhibitors (Watson et al, 2001;Asano et al, 2000). All potent inhibitors of NAGs in this class have hitherto been pyranose analogues of NAG such as the piperidine (1) (Fleet et al, 1986) and NAG-thiazoline (Knapp et al, 1996); other heterocyclic compounds containing a pyranose ring (Terinek & Vasella, 2005;van den Berg et al, 2004) also show promise as potential chemotherapeutic agents. In contrast few five-ring pyrrolidine analogues, none of which are potent, have been reported (Croucher et al, 1994;Liessem et al, 1993;Liu et al, 2004).…”

A Selective Inhibitor Gal‐PUGNAc of Human Lysosomal β‐Hexosaminidases Modulates Levels of the Ganglioside GM2 in Neuroblastoma Cells

“…Gal‐PUGNAc 1 is therefore comparable to the most potent inhibitors of family 20 β‐hexosaminidases that have K i values in the low nanomolar range (see Supporting Information) 11. 20, 21…”