ABSTRACT
A series of pentahydroxylated pyrrolidines, displaying five contiguous stereogenic centres and epimeric to α-glucosidase inhibitor homoDMDP, have been synthesized. The key step involves a γ-aminoalcohol rearrangement applied to polyhydroxylated azepanes. These five-membered iminosugars demonstrate micromolar inhibition of glycosidases.
Subject(s)
Amino Alcohols/chemistry , Azepines/chemistry , Glycoside Hydrolase Inhibitors/chemical synthesis , Mannitol/analogs & derivatives , Pyrrolidines/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Imino Pyranoses/chemical synthesis , Imino Pyranoses/chemistry , Imino Pyranoses/pharmacology , Mannitol/chemical synthesis , Mannitol/chemistry , Mannitol/pharmacology , Molecular Structure , Pyrrolidines/chemistry , Structure-Activity Relationship , alpha-Glucosidases/metabolismABSTRACT
Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER α-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on α-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER α-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases α-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of α-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from α-glucosidase inhibition.
Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Glycoside Hydrolase Inhibitors , Imino Sugars/chemistry , 1-Deoxynojirimycin/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cattle , Cell Survival/drug effects , Click Chemistry , Diarrhea Viruses, Bovine Viral/metabolism , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosamine/analogs & derivatives , Glucosamine/chemistry , Glycosylation , Hepacivirus/metabolism , Imino Sugars/chemical synthesis , Imino Sugars/pharmacology , Madin Darby Canine Kidney Cells , Viral Envelope Proteins/metabolism , Virus Replication/drug effects , alpha-Glucosidases/metabolismABSTRACT
Triisobutylaluminum-promoted rearrangement of unsaturated glycosides containing electron-donating aglycons-such as C-aryl glycoside 1, or O-, S-, and Se-glycosides-provides direct access to highly functionalized cyclohexane derivatives such as 2.
