Functionalized pyrrolidine inhibitors of human type II alpha-mannosidases as anti-cancer agents: optimizing the fit to the active site.
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.
Fiaux
Hélène
H
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Kuntz
Douglas A
DA
Hoffman
Daniela
D
Janzer
Robert C
RC
Gerber-Lemaire
Sandrine
S
Rose
David R
DR
Juillerat-Jeanneret
Lucienne
L
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*
D000970:Antineoplastic Agents; D011759:Pyrrolidines; D043323:alpha-Mannosidase