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001-es BibID:BIBFORM062009
Első szerző:Goyard, David
Cím:Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition / David Goyard, Bálint Kónya, Aikaterini S. Chajistamatiou, Evangelia D. Chrysina, Jérémy Leroy, Sophie Balzarin, Michel Tournier, Didier Tousch, Pierre Petit, Cédric Duret, Patrick Maurel, László Somsák, Tibor Docsa, Pál Gergely, Jean-Pierre Praly, Jacqueline Azay-Milhau, Sébastien Vidal
Dátum:2016
ISSN:0223-5234 1768-3254
Megjegyzések: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 ?M. 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 ?M), compared to that of the O-unprotected analog (19.95 ?M). 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.
Tárgyszavak:Természettudományok Kémiai tudományok Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Carbohydrates
Spiro-isoxazolines
Glycogen phosphorylase inhibitors
Hepatocytes
Zucker rats
Hepatic glucose production
Type 2 diabetes
Megjelenés:European Journal of Medicinal Chemistry 108 (2016), p. 444-454. -
További szerzők:Kónya Bálint (1984-) (vegyész) Chajistamatiou, Aikaterini S. Chrysina, Evangelia D. Leroy, Jérémy Balzarin, Sophie Tournier, Michel Tousch, Didier Petit, Pierre Duret, Cédric Maurel, Patrick Somsák László (1954-) (vegyész) Docsa Tibor (1975-) (vegyész, biokémikus) Gergely Pál (1947-) (biokémikus) Praly, Jean-Pierre Azay-Milhau, Jacqueline Vidal, Sébastien
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001-es BibID:BIBFORM039219
Első szerző:Goyard, David
Cím:Synthesis of 1,2,3-triazoles from xylosyl and 5-thioxylosyl azides : evaluation of the xylose scaffold for the design of potential glycogen phosphorylase inhibitors / Goyard David, Baron Marc, Skourti Paraskevi V., Chajistamatiou Aikaterini S., Docsa Tibor, Gergely Pál, Chrysina Evangelia D., Praly Jean-Pierre, Vidal Sébastien
Dátum:2012
ISSN:0008-6215
Megjegyzések:Various acetylenic derivatives and acetylated β-d-xylopyranosyl azide or the 5-thio-β-d-xylopyranosyl analogue were coupled by Cu(I)-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) to afford a series of 1-xylosyl-4-substituted 1,2,3-triazoles. Controlled oxidation of the endocyclic sulfur atom of the 5-thioxylose moiety led to the corresponding sulfoxides and sulfones. Deacetylation afforded 19 hydroxylated xylose and 5-thioxylose derivatives, found to be only sparingly water-soluble. Compared to glucose-based analogues, they appeared to be much weaker inhibitors of glycogen phosphorylase, as the absence of a hydroxymethyl group weakens their binding at the enzyme active site. However, such new xylose derivatives might be useful glycomimetics.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Carbohydrate Research. - 364 (2012), p. 28-40. -
További szerzők:Baron, Marc Skourti, Paraskevi V. Chajistamatiou, Aikaterini S. Docsa Tibor (1975-) (vegyész, biokémikus) Gergely Pál (1947-) (biokémikus) Chrysina, Evangelia D. Praly, Jean-Pierre Vidal, Sébastien
Pályázati támogatás:CNK 80709
OTKA
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DOI
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