title: Functionalized pyrrolidine inhibitors of human type II alpha-mannosidases as anti-cancer agents: optimizing the fit to the active site.
abstract: Refining the chemical structure of functionalized pyrrolidine-based inhibitors of Golgi alpha-mannosidase II (GMII) to optimize binding affinity provided a lead molecule that demonstrated nanomolar competitive inhibition of alpha-mannosidases II and an optimal fit in the active site of Drosophila GMII by X-ray crystallography. Esters of this lead compound also inhibited the growth of human glioblastoma and brain-derived endothelial cells more than the growth of non-tumoral human fibroblasts, suggesting their potential for anti-cancer therapy.
authors.affiliation: Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Fiaux
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kuntz
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoffman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Janzer
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gerber-Lemaire
authors.forename: David R
authors.initials: DR
authors.lastname: Rose
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004330:Drosophila / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects; D007887:Fabaceae / Q000201:enzymology; D005909:Glioblastoma; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D043323:alpha-Mannosidase / Q000037:antagonists & inhibitors* / Q000145:classification*
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; D043323:alpha-Mannosidase