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: Hélène Fiaux, Douglas A Kuntz, Daniela Hoffman, Robert C Janzer, Sandrine Gerber-Lemaire, David R Rose, Lucienne Juillerat-Jeanneret
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 15 Pg. 7337-46 (Aug 01 2008) ISSN: 1464-3391 [Electronic] England
• PMID: 18599296 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Pyrrolidines
• alpha-Mannosidase

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Drosophila (enzymology)
• Endothelial Cells (drug effects)
• Fabaceae (enzymology)
• Glioblastoma
• Humans
• Models, Molecular
• Molecular Structure
• Pyrrolidines (chemistry, pharmacology)
• Structure-Activity Relationship
• alpha-Mannosidase (antagonists & inhibitors, classification)