Abstract
Here, the synthesis and glycosidase inhibition properties of the two first known 3-ethyloctahydro-1H-indole-4,5,6-triols are reported. This study shows the transformation of d-glucose into polyhydroxylated 1-(2-nitrocyclohexane) acetaldehydes, followed by a protocol involving the formation of the azacyclopentane ring. Results of inhibitory potency assays and docking calculations show that at least one of them could be a lead for optimization in the search for compounds that behave like folding chaperones in lysosomal storage diseases.
Highlights
Iminosugars [1,2,3,4] and aminocarbasugars [5,6,7] are sugar mimics that inhibit a variety of enzymes of therapeutic interest, including glycosidases and glycosyltransferases
Most of the scoring values in the docking results for galactose are colored with a single color, to indicate that there seems to be a consensus on the pose reached by these compounds, which reproduces the one found in the crystal structure of the β-galactosidase-galactose complex found in Protein Data Bank (PDB) entry 3HTC
This work presents new synthetic routes to polyhydroxylated octahydroindoles with pharmacological chaperone (PC) therapeutic potential aimed at autosomal recessive diseases like GM1 gangliosidosis and Morquio B, a group of lysosomal storage disorders resulting from the abnormal metabolism of macro-substances such as glycosphingolipids, glycogen, mucopolysaccharides, and glycoproteins [33]
Summary
Iminosugars [1,2,3,4] and aminocarbasugars [5,6,7] are sugar mimics that inhibit a variety of enzymes of therapeutic interest, including glycosidases and glycosyltransferases They have been shown to be lead molecules for the treatment of diseases such as diabetes, viral infections, or lysosomal storage disorders. The bicyclic iminosugar castanospermine (V) [16,17] is a polyhydroxylated indolizidine alkaloid [3,18] that can be considered as a conformational restricted analogue of miglitol This compound and its derivatives have received considerable attention as potential antineoplastic and immunosuppressive agents, but, they have shown toxicity to human cells [19,20,21,22].
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