title: CuAAC click chemistry with N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol provides access to triazole-linked piperidine and azepane pseudo-disaccharide iminosugars displaying glycosidase inhibitory properties.
abstract: Protecting group-free synthesis of 1,2:5,6-di-anhydro-D-mannitol, followed by ring opening with propargylamine and subsequent ring closure produced a separable mix of piperidine N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and azepane N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol. In O-acetylated form, these two building blocks were subjected to CuAAC click chemistry with a panel of three differently azide-substituted glucose building blocks, producing iminosugar pseudo-disaccharides in good yield. The overall panel of eight compounds, plus 1-deoxynojirimycin (DNJ) as a benchmark, was evaluated as prospective inhibitors of almond β-glucosidase, yeast α-glucosidase and barley β-amylase. The iminosugar pseudo-disaccharides showed no inhibitory activity against almond β-glucosidase, while the parent N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol likewise proved to be inactive against yeast α-glucosidase. Inhibitory activity could be reinstated in the former series by appropriate substitution on nitrogen. The greater activity of the piperidine could be rationalized based on docking studies. Further, potent inhibition of β-amylase was observed with compounds from both the piperidine and azepane series.
authors.affiliation: School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, Ribeirão Preto 14040-930, Brazil.
authors.forename: Luís Otávio B
authors.initials: LO
authors.lastname: Zamoner
authors.affiliation: School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, Ribeirão Preto 14040-930, Brazil.
authors.forename: Valquíria
authors.initials: V
authors.lastname: Aragão-Leoneti
authors.affiliation: School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, Ribeirão Preto 14040-930, Brazil.
authors.forename: Susimaire P
authors.initials: SP
authors.lastname: Mantoani
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rugen
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Nepogodiev
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Field
authors.affiliation: School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, Ribeirão Preto 14040-930, Brazil. Electronic address: carronal@usp.br.
authors.forename: Ivone
authors.initials: I
authors.lastname: Carvalho
mesh_terms: D017485:1-Deoxynojirimycin / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D057930:Click Chemistry / Q000379:methods; D004187:Disaccharides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D001467:Hordeum / Q000737:chemistry / Q000201:enzymology; D050111:Imino Sugars / Q000138:chemical synthesis* / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D010293:Pargyline / Q000031:analogs & derivatives / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D011437:Propylamines / Q000737:chemistry; D000068181:Prunus dulcis / Q000737:chemistry / Q000201:enzymology; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000201:enzymology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry; D000520:alpha-Glucosidases / Q000737:chemistry*; D001614:beta-Amylase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D001386:Azides; D004187:Disaccharides; D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D050111:Imino Sugars; D010880:Piperidines; D011437:Propylamines; D014230:Triazoles; D017485:1-Deoxynojirimycin; C009054:propargylamine; D008353:Mannitol; D010293:Pargyline; D001614:beta-Amylase; D000520:alpha-Glucosidases; D001617:beta-Glucosidase; D005947:Glucose
keywords: Click chemistry; CuAAC reaction; Glycosidase inhibition; Pseudo-disaccharide iminosugars