title: Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition.
abstract: Glycogen phosphorylase (GP) is a target for the treatment of hyperglycaemia in the context of type 2 diabetes. This enzyme is responsible for the depolymerization of glycogen into glucose thereby affecting the levels of glucose in the blood stream. Twelve new d-glucopyranosylidene-spiro-isoxazolines have been prepared from O-peracylated exo-D-glucals by regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides generated in situ by treatment of the corresponding oximes with bleach. This mild and direct procedure appeared to be applicable to a broad range of substrates. The corresponding O-unprotected spiro-isoxazolines were evaluated as glycogen phosphorylase (GP) inhibitors and exhibited IC50 values ranging from 1 to 800 μM. Selected inhibitors were further evaluated in vitro using rat and human hepatocytes and exhibited significant inhibitory properties in the primary cell culture. Interestingly, when tested with human hepatocytes, the tetra-O-acetylated spiro-isoxazoline bearing a 2-naphthyl residue showed a much lower IC50 value (2.5 μM), compared to that of the O-unprotected analog (19.95 μM). The most promising compounds were investigated in Zucker fa/fa rat model in acute and sub-chronic assays and decreased hepatic glucose production, which is known to be elevated in type 2 diabetes. This indicates that glucose-based spiro-isoxazolines can be considered as anti-hyperglycemic agents in the context of type 2 diabetes.
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622, Villeurbanne, France.
authors.forename: David
authors.initials: D
authors.lastname: Goyard
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010, Debrecen, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Kónya
authors.affiliation: Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens, GR-11635, Greece.
authors.forename: Aikaterini S
authors.initials: AS
authors.lastname: Chajistamatiou
authors.affiliation: Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens, GR-11635, Greece.
authors.forename: Evangelia D
authors.initials: ED
authors.lastname: Chrysina
authors.affiliation: Université Montpellier 1, EA7288, Centre de Pharmacologie et Innovation dans le Diabète, Montpellier, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Leroy
authors.affiliation: Université Montpellier 1, EA7288, Centre de Pharmacologie et Innovation dans le Diabète, Montpellier, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Balzarin
authors.affiliation: Université Montpellier 1, EA7288, Centre de Pharmacologie et Innovation dans le Diabète, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tournier
authors.affiliation: Université Montpellier 1, EA7288, Centre de Pharmacologie et Innovation dans le Diabète, Montpellier, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Tousch
authors.affiliation: Université Montpellier 1, EA7288, Centre de Pharmacologie et Innovation dans le Diabète, Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Petit
authors.affiliation: INSERM, U1040, F-34295, Montpellier, France; Université Montpellier 1, UMR 1040, F-34295, Montpellier, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Duret
authors.affiliation: INSERM, U1040, F-34295, Montpellier, France; Université Montpellier 1, UMR 1040, F-34295, Montpellier, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.affiliation: Department of Organic Chemistry, University of Debrecen, POB 20, H-4010, Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Somsák
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032, Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Docsa
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032, Debrecen, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Gergely
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622, Villeurbanne, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Praly
authors.affiliation: Université Montpellier 1, EA7288, Centre de Pharmacologie et Innovation dans le Diabète, Montpellier, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Azay-Milhau
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622, Villeurbanne, France. Electronic address: sebastien.vidal@univ-lyon1.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Vidal
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D011924:Rats, Zucker; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007555:Isoxazoles; D013141:Spiro Compounds; D024981:Glycogen Phosphorylase; D005947:Glucose
keywords: Carbohydrates; Glycogen phosphorylase inhibitors; Hepatic glucose production; Hepatocytes; Spiro-isoxazolines; Type 2 diabetes; Zucker rats