sp²‐Iminosugar O‐, S‐, and N‐Glycosides as Conformational Mimics of α‐Linked Disaccharides; Implications for Glycosidase Inhibition

Abstract

The synthesis of mimics of the α(1→6)‐ and α(1→4)‐linked disaccharides isomaltose and maltose featuring a bicyclic sp2‐iminosugar nonreducing moiety O‐, S‐, or N‐linked to a glucopyranoside residue is reported. The strong generalized anomeric effect operating in sp2‐iminosugars determines the α‐stereochemical outcome of the glycosylation reactions, independent of the presence or not of participating protecting groups and of the nature of the heteroatom. It also imparts chemical stability to the resulting aminoacetal, aminothioacetal, or gem‐diamine functionalities. All the three isomaltose mimics behave as potent and very selective inhibitors of isomaltase and maltase, two α‐glucosidases that bind the parent disaccharides either as substrate or inhibitor. In contrast, large differences in the inhibitory properties were observed among the maltose mimics, with the O‐linked derivative being a more potent inhibitor than the N‐linked analogue; the S‐linked pseudodisaccharide did not inhibit either of the two target enzymes. A comparative conformational analysis based on NMR and molecular modelling revealed remarkable differences in the flexibility about the glycosidic linkage as a function of the nature of the linking atom in this series. Thus, the N‐pseudodisaccharide is more rigid than the O‐linked derivative, which exhibits conformational properties very similar to those of the natural maltose. The analogous pseudothiomaltoside is much more flexible than the N‐ or O‐linked derivatives, and can access a broader area of the conformational space, which probably implies a strong entropic penalty upon binding to the enzymes. Together, the present results illustrate the importance of taking conformational aspects into consideration in the design of functional oligosaccharide mimetics.

Fullerene‐sp2‐Iminosugar Balls as Multimodal Ligands for Lectins and Glycosidases: A Mechanistic Hypothesis for the Inhibitory Multivalent Effect

“…In this study we have instead selected the 1-amino-5N,6O-oxomethylydenenojirimycin (1N-ONJ) and its C2 epimer 1-amino-5N,6O-oxomethylydenemannnojirimycin (1N-OMJ), ]37-39] two representatives of the so-called sp 2 -iminosugar glycosidase inhibitors family [40][41][42][43] with ''mismatching'' and ''matching'' relationships with a-mannosidase, respectively, as the inhitope motifs. In agreement with their hydroxylation profiles, the first one has proven to impart selective inhibitory properties towards a-glucosidase in monovalent form (e.g., 5), [37][38][39] whereas the second strongly promoted inhibition of a-mannosidase (e.g., 6; Figure 2). [37] By presenting them in a multivalent manner (11)(12)(13)(14) and evaluating their glycosidase inhibition abilities in comparison with monovalent references (7-10) we intended to scrutinize the scope of the inhibitory multivalent effect and how it is affected by the individual affinity of the ligands towards the target enzyme.…”

“…Exclusively, the diastereomer having the pseudo-anomeric substituent in an axial orientation, matching the configuration of a-d-glucopyranosides, was detected in both cases, which is in agreement with the strong orbital contribution to the generalized anomeric effect [47] previously observed in related sp 2 -iminosugar gemdiamines. [37][38][39] The clickable azide-armed derivatives 25 and 26 were accessed by Boc hydrolysis (!21 and 22) followed by diazo-transfer reaction. [48] To prepare the monovalent 1N-ONJ clicked adducts 7 and 8 as control compounds, heterogeneous CuAAC with 1-pentine was next effected by using CuI as the catalyst (Scheme 1).…”

Structural Basis of Pharmacological Chaperoning for Human β-Galactosidase

“…Actually this compound is a rather selective inhibitor of ␤-glucosidase (21). Whereas 6S-NBI-GJ has been shown to exist exclusively in the 4 C 1 chair conformation in water solution, with OH1 axially oriented in the ␣-configuration (34,35), in the corresponding complex with ␤-Gal the opposite ␤-configuration was encountered, with the 6-membered ring and the 5-membered ring in the same plane (supplemental Fig. S4).…”

Conformationally-Locked N-Glycosides with Selective β-Glucosidase Inhibitory Activity: Identification of a New Non-Iminosugar-Type Pharmacological Chaperone for Gaucher Disease

“…Actually, they can be formally considered as conformationally locked N-glycoside derivatives, which should warrant chemical and enzymatic stability and at the same time impart selectivity. 60 On the other hand, similar to compounds 2 and 3 bearing an imine type nitrogen, the PSO structure is also very well suited for the incorporation of a broad battery of substituents on the exocyclic heteroatom. Here we report the synthesis of the key synthetic precursor, the scope of the approach, the assessment of the affinity and selectivity of the final compounds against a panel of commercial glycosidases, and the evaluation of a selected candidate as pharmacological chaperone in human Gaucher disease fibroblasts.…”