Glycosidase Inhibitors and Synthetic Strategies

Glycosidase inhibitors are molecules designed to bind and block glycosidase enzymes, thereby modulating carbohydrate processing in biological systems. Among the most studied are iminosugars, in which a ring oxygen is replaced by nitrogen to mimic the transition state of glycosidic bond hydrolysis. Natural products and synthetic analogues of these scaffolds have found applications in the treatment of diabetes, lysosomal storage disorders, viral infections and as pharmacological chaperones. Synthetic strategies have evolved from linear, multi-step sequences using protected sugars to diversity-oriented methods that employ catalytic, stereoselective transformations and late-stage functionalisation. Key developments include organometallic-catalysed C–N bond formation, tethered aminohydroxylation approaches and chemoenzymatic cascades, all delivering high levels of regio- and stereocontrol. Integration of computational modelling with high-throughput screening has refined structure–activity relationships, enabling the rational design of isoform-selective inhibitors. By enabling the design of selective inhibitors targeting distinct glycosidase isoforms, these advances have broad implications for treating metabolic disorders and viral infections worldwide.

Research from Nature Portfolio

A landmark synthetic route has been developed that transforms simple acetaldehyde derivatives into a broad spectrum of iminosugars and imino-C-nucleoside analogues in only two to three steps. This strategy combines operational simplicity with high enantio- and diastereoselectivity across diverse substrates, including indolizidine and pyrrolizidine frameworks. The concise sequence is fully compatible with diversity-oriented synthesis, facilitating rapid generation of compound libraries for biological screening. Applied at scale, it has yielded multiple lead candidates exhibiting submicromolar inhibitory activity against key glycosidases. The convergence of this synthetic efficiency with high-throughput screening demonstrates a powerful platform for accelerating drug discovery efforts in glycoscience.

Glycosidase Inhibitors and Synthetic Strategies publication trend

The graph below shows the total number of articles in glycosidase inhibitors and synthetic strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Glycosidase inhibitors: Molecules that bind and inhibit glycosidase enzymes, disrupting carbohydrate hydrolysis.

Iminosugars: Sugar analogues in which a ring oxygen is replaced by nitrogen, often acting as transition-state mimics.

Tethered aminohydroxylation: A synthetic reaction that forms C–N and C–O bonds in a single step by linking substrates to a catalyst via a tether.

Diastereoselectivity: Preferential formation of one diastereomer over others in a chemical reaction.

Diversity-oriented synthesis: Strategy to rapidly generate molecular libraries with high structural diversity for screening.

References

1. Stereoselective Synthesis of Heavily Hydroxylated Azepane Iminosugars via Osmium-Catalyzed Tethered Aminohydroxylation. Organic Letters (2023).
2. Direct synthesis of imino-C-nucleoside analogues and other biologically active iminosugars. Nature Communications (2015).
3. Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase). The Journal of Organic Chemistry (2021).