title: Hydroxymethyl-Branched Polyhydroxylated Indolizidines: Novel Selective α-Glucosidase Inhibitors.
abstract: α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound 9b exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding.
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Boisson
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Amélia
authors.initials: A
authors.lastname: Thomasset
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Racine
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cividino
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Banchelin Sainte-Luce
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Poisson
authors.affiliation: §Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims (ICMR), CNRS UMR 7312, UFR Sciences Exactes et Naturelles, BP 1039, 51687 Reims Cedex 2, France.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Behr
authors.affiliation: †Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France.|‡CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Py
mesh_terms: D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054836:Indolizidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D054836:Indolizidines; D010880:Piperidines; D000520:alpha-Glucosidases