Sphingofungin-based aminopolyols and DIX-like azasugars - their synthesis and in vitro biological profile

A simple stereodivergent approach to sphingofungin-based aminopolyols and their modification into 1,5-dideoxy-1,5-iminoxylitol (DIX)-based 1-N-iminosugars was accomplished. The use of a [3,3]-heterosigmatropic rearrangement on carbohydrate scaffolds, followed by Grubbs metathesis chemistry, provided an efficient route to isomeric sphingofunginols as advanced intermediates for the construction of C-alkyl-DIX analogues. The suitable position of both the amino and primary hydroxyl groups enabled the 6-exo-tet type of cyclisation, leading to a piperidine ring. The target molecules were screened in vitro for their cytotoxic potency on a panel of human malignant cell lines. The (2R)-configured DIX-like analogue exhibited a strong capacity to inhibit proliferation of the leukaemia cells (Jurkat), with an IC₅₀ value of 0.88 μM. The same compound demonstrated remarkable cytotoxic behaviour against melanoma and HeLa cells. On the other hand, isosphingofunginols have only a moderate ability to inhibit malignant proliferation. The glycosidase inhibition study identified both iminosugars 49 and 58 as inhibitors of almond β-glucosidase (IC₅₀ = 6.5 μM and 5.5 μM, respectively). Based on the literature findings, demonstrating potent inhibition of human β-glucocerebrosidase (GCase) by structurally related long-chain trihydroxylated piperidines, compounds 49 and 58 were evaluated as potential GCase ligands by molecular docking.