English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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 S N 2 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 IC 50 41 µM and 138 µM, respectively, using DNJ as reference (IC 50 134 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 IC 50 109 and 184 µM, respectively, comparable to miglustat with the same N -butyl substituent ( 40a , IC 50 172 µM). Interestingly, the seven-membered ring L- ido -azepane ( 40b) displayed near twice the activity (IC 50 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 IC 50 of 4 µM.

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