Diversity-oriented synthesis and study of triazole-fused bicyclic iminosugars

Triazole-fused bicyclic iminosugars were synthesized from D-glucose using a Cu-free intramolecular azide-alkyne cycloaddition (IAAC)-derived tetracyclic diversity-oriented synthetic scaffold. This scaffold was used as a common intermediate for the synthesis of iminosugars that differ from known glycosidase inhibitors by the addition of a nitrogen atom within the triazole and pyranose rings. To make the synthesis efficient, this synthetic strategy employs the use of multiple one-pot multi-step chemical transformations and water as a solvent/co-solvent in the key synthetic transformations. Molecular docking studies revealed that a few of the synthesized compounds exhibit strong interaction with glycosidases (up to -10.1 kcal mol^-1), suggesting potential inhibitory activity. This was supported by enzymatic assays against seven glycosidases, where four triazole-fused bicyclic iminosugars showed inhibition (IC₅₀: 0.17-0.54 mM), demonstrating partial correlation with docking studies. Among the four systems, a tetracyclic C-5 azido compound 13 showed significant inhibition of α-glucosidase and α-mannosidase (K_i = 0.08-0.21 mM). Interestingly, although the cytotoxicity studies did not correlate with the enzyme inhibition data, compounds 17 and 19 showed selective activity (IC₅₀: 0.13-0.5 mM) against cancer cell lines MDA-MB-231, PC3 and WRL68. These findings suggest distinct mechanisms of action and identify promising separate leads for enzymatic and anticancer applications.