Inhibition of Glycosidases by Lactam Oximes: Influence of the Aglycon in Disaccharide Analogues

Abstract

The influence of a substituent at the hydroximo function of the lactam analogue 1 on the inhibition of β‐ and α‐glucosidases is evaluated. In contrast to 1, the O‐alkyl oximes 5, 6, 9, and 10 are selective inhibitors of β‐glucosidases. Alkylation of the D‐gluconohydroximo‐1,5‐lactam 19 with the triflate 12, or condensation of the thiogluconolactam 20 with the hydroxylamines 14 or 18 afforded the benzylated cellobioside analogues 21 and 23, respectively. The O‐alkyl oximes 33 and 39 were prepared similarly (Scheme 3). Deprotection afforded the cellobioside analogues 5 and 6, and the O‐alkyl oximes 9 and 10. The lactam O‐alkyl oximes 5, 6, 9, and 10 are strong inhibitors of the β‐glucosidase from C. saccharolyticum (IC50=0.3 – 8 μM) and, with exception of the dodecyl analogue 9 (IC50=2 μM), moderate‐to‐weak inhibitors of β‐glucosidases from sweet almond (IC50=60 – 1000 μM; see Table). In contrast to the strong inhibition of α‐glucosidase from brewer's yeast by 1 (Ki=2.9 μM), the ethers 5, 6, and 10 are weak inhibitors of this enzyme (IC50 between 2500 and >5000 μM). Similarly, the D‐galactohydroximo‐1,5‐lactam 7 is a potent inhibitor of the α‐galactosidase from coffee beans and of the β‐galactosidases from bovine liver and E. coli (Ki=5, 10, and 0.1 μM, resp.), while the lactoside analogue 8 is a strong inhibitor of the E. coli β‐galactosidase (Ki=0.1 μM), but a moderate‐to‐weak inhibitor of coffee‐bean α‐galactosidase and bovine‐liver β‐galactosidase (Ki=250 μM and IC50=2500 μM, resp.). The galacto‐configured lactam oximes 7 and 8 are good inhibitors of the β‐glucosidase isolated from C. saccharolyticum (Ki=2.5 and 3.3 μM, resp.).

A surface endogalactanase in Bacteroides thetaiotaomicron confers keystone status for arabinogalactan degradation

“… 5-Amino-2,3,4,6-tetra- O -benzyl-5-deoxy-1-thio-D-galactono-1,5-lactam32 (61.5 mg, 0.111 mmol) was dissolved in aminoacetaldehyde dimethyl acetal (0.18 mL, 1.652 mmol) and stirred under N 2 for 24 h. The mixture was diluted with EtOAc (20 mL) and washed with H 2 O (2 × 20 mL) and brine (1 × 20 mL). The organic extracts were dried (MgSO 4 ) and then concentrated under reduced pressure.…”

Glycosidase inhibition: assessing mimicry of the transition state

“…Amidine inhibitors, such as the gluco form 13 , were synthesised in the Ganem group in the early 1990s,108 followed by amidrazone and amidoxime (also called hydroximo-1,5-lactam or 1,5-lactam oxime) derivatives, in gluco ​ 14 ,​ manno and galacto forms,109,110 which were shown to inhibit both α- and β-glycosidases 110,111. A number of functional groups have been added to the exocyclic nitrogen in order to mimic the aglycon, both with the amidine112-114 and amidoxime/hydroximolactam115,116 inhibitors. In addition the latter has also been synthesised in an oligosaccharide form 117.…”

Recent Developments of Transition-State Analogue Glycosidase Inhibitors of Non-Natural Product Origin

“…Various groups have synthesized and tested amidine and amidoxime derivatives where the substituent at the exocyclic nitrogen has been varied [164][165][166][167][168][169][170][171] These substituents are supposed to mimic the aglycon in the natural substrates, thereby enhancing the selectivity and inhibitory properties of the compounds. However, they have only succeeded in improving the selectivity, and the K i values are comparable with the K i value of the corresponding monosaccharide analogues (Tables 35-37).…”

“…The first two examples of these compounds, the glucose and mannose analogues 2 and 3 (Table 45), were found to have a halfchair conformation and inhibit glycosidases moderately, though 2 inhibited β-glucosidase and β-galactosidase with a K i of about 1.5 µM. 170 Interestingly, a log(k cat /K M ) vs log K i plot for the inhibitors 2 and 3 and for the hydrolysis reaction of 4-nitrophenyl glucoside or mannoside by a series of different glycosidases gave a linear relationship. This suggests a similarity between the transition state of these different enzyme-catalyzed reactions and the inhibitors at least in regard to the changes made in the inhibitor and substrate/enzyme pair.…”

“…These compounds have an estimated p K a value of −4 and cannot be expected to be fully protonated in the active site. The first two examples of these compounds, the glucose and mannose analogues 2 and 3 (Table ), were found to have a half-chair conformation and inhibit glycosidases moderately, though 2 inhibited β-glucosidase and β-galactosidase with a K i of about 1.5 μM . Interestingly, a log( k cat / K M ) vs log K i plot for the inhibitors 2 and 3 and for the hydrolysis reaction of 4-nitrophenyl glucoside or mannoside by a series of different glycosidases gave a linear relationship.…”