title: Synthesis of 1,5-dideoxy-1,5-iminoribitol C-glycosides through a nitrone-olefin cycloaddition domino strategy: identification of pharmacological chaperones of mutant human lysosomal β-galactosidase.
abstract: We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar C-glycosides 7a-e and 8. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines 10a-e in a "one-pot" protocol. The iminoribitol C-glycosides 7a-e and 8 were found to be modest β-galactosidase (bGal) inhibitors. However, compounds 7c and 7e showed "pharmacological chaperone" activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2-6-fold.
authors.affiliation: Department of Chemistry, Garware Research Centre, and ⊥Institute of Bioinformatics and Biotechnology, University of Pune , Pune 411007, India.
authors.forename: Aloysius
authors.initials: A
authors.lastname: Siriwardena
authors.forename: Dhiraj P
authors.initials: DP
authors.lastname: Sonawane
authors.forename: Omprakash P
authors.initials: OP
authors.lastname: Bande
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Markad
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yonekawa
authors.forename: Michael B
authors.initials: MB
authors.lastname: Tropak
authors.forename: Sougata
authors.initials: S
authors.lastname: Ghosh
authors.forename: Balu A
authors.initials: BA
authors.lastname: Chopade
authors.forename: Don J
authors.initials: DJ
authors.lastname: Mahuran
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Dhavale
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D061565:Cycloaddition Reaction; D005347:Fibroblasts / Q000737:chemistry*; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006027:Glycosides; D006801:Humans; D008247:Lysosomes / Q000737:chemistry* / Q000378:metabolism; D018832:Molecular Chaperones / Q000494:pharmacology* / Q000627:therapeutic use*; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D009589:Nitrogen Oxides / Q000737:chemistry*; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000475:Alkenes; C438934:C-glycoside; D006027:Glycosides; D018832:Molecular Chaperones; D009005:Monosaccharides; D009589:Nitrogen Oxides; C015388:nitrones; D001616:beta-Galactosidase