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

Abstract

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.