title: Imino sugars that are less toxic but more potent as antivirals, in vitro, compared with N-n-nonyl DNJ.
abstract: Imino sugar glucosidase inhibitors have selective antiviral activity against certain enveloped, mammalian viruses. Deoxynojirimycins (DNJs) modified by N-alkylation to contain a nine carbon atom side chain (N-n-nonyl-deoxynojirimycin; N-nonyl-DNJ, NN-DNJ) were shown to be, for example, at least 20 times more potent in inhibiting hepatitis B virus (HBV) and bovine viral diarrhoea virus (BVDV) in cell based assays than the non-alkylated DNJ. These data suggested that modification of the alkyl side chain could influence antiviral activity. Previous work has focused on varying side chain length. In this report, the influence of side chain branching and cyclization upon toxicity and antiviral activity was explored. Briefly, using a virus secretion assay for HBV and a single step growth (yield reduction) assay for BVDV, 14 different DNJ-based sugars, possessing various N-alkyl substitutions, were tested for antiviral activity. Of the series, N-methoxy-nonyl-DNJ and N-butyl-cyclohexyl DNJ were determined to have the best selectivity index against BVDV and HBV, with the N-methoxy analogue being the most potent with micromolar antiviral activity. The results of this antiviral survey and the implications for the mechanism of action and ultimate therapeutic potential of the DNJ-based imino sugars is provided and discussed.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, The Jefferson Center of Thomas Jefferson University, Doylestown, Pa., USA. anand.mehta@mail.tju.edu
authors.forename: Anand
authors.initials: A
authors.lastname: Mehta
authors.forename: Serguey
authors.initials: S
authors.lastname: Ouzounov
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Ender
authors.initials: E
authors.lastname: Simsek
authors.forename: Xuanyong
authors.initials: X
authors.lastname: Lu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Moriarty
authors.forename: Gary
authors.initials: G
authors.lastname: Jacob
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000633:toxicity; D000478:Alkylation; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002241:Carbohydrates / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D003500:Cyclization; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure
chemical_list: D000998:Antiviral Agents; D002241:Carbohydrates; C112150:N-nonyl-1-deoxynojirimycin; D017485:1-Deoxynojirimycin; D005944:Glucosamine; C013626:nojirimycin