Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

Abstract

N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC50 41 µM and 138 µM, respectively, using DNJ as reference (IC50 134 µM). On the other hand, β-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 µM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 µM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 µM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-glucosidase inhibitors of the series with IC50 of 4 µM.

Synthesis and Evaluation of Novel Iminosugars Prepared from Natural Amino Acids

“…Regarding the inhibitory results, we can conclude that these compounds are very weak inhibitors only against certain enzymes far from the inhibition values of well-known iminosugars such as deoxinojirimycin [ 35 ] or castanospermine analogs [ 36 ]. However, the activation observed in certain cases deserves some comments, as there are few precedents of this behavior [ 37 , 38 ], including our previous results with similar compounds [ 10 ].…”

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

“…Imino sugars were described as potent and specific activators of the electrogenic properties of SGLT3. Interestingly, imino sugars are also used to treat type 2 diabetes and lysosomal storage diseases based on their inhibition of α-glucosidases and glucosyltransferases [211]. Imino sugars may serve as tool compounds to explore the precise physiological role of SGLT3 [190].…”

Determination of 1-Deoxynojirimycin (1-DNJ) in Leaves of Italian or Italy-Adapted Cultivars of Mulberry (Morus sp.pl.) by HPLC-MS

“…Among natural products extracted from plants and other sources, iminosugars are analogs of sugars in which an atom of nitrogen replaces the ring oxygen atom. This substitution results in the inhibition of glycosidases and glycosyltransferases, therefore preventing normal carbohydrate metabolism [ 2 ]. The compound 1-Deoxynojirimycin (1-DNJ) is one of the most popular iminosugars and was first extracted from mulberry ( Morus sp.pl.)…”