Functionalized pyrrolidine inhibitors of human type II alpha-mannosidases as anti-cancer agents: Optimizing the fit to the active site.
Bioorganic & medicinal chemistry 2008 Jun 14; In press
Fiaux H H, Kuntz D DA, Hoffman D D, Janzer R RC, Gerber-Lemaire S S, Rose D DR, Juillerat-Jeanneret L L
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
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.
Keywords: alpha-mannosidase