Functionalized pyrrolidine inhibitors of human type II α-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. broblasts, suggesting their potential for anti-cancer therapy. (C) 2008 Elsevier Ltd. All rights reserved.