Functionalized pyrrolidines inhibit alpha-mannosidase activity and growth of human glioblastoma and melanoma cells.

Abstract

New substituted pyrrolidine-3,4-diol derivatives were prepared from d-(-)- and l-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases were determined. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol ((+)-7a) was a potent and selective inhibitor of jack bean alpha-mannosidase (K(i) = 135 nM). However, when evaluated on human tumor cells, 7a, and the reference compound swainsonine, did not efficiently inhibit the growth of glioblastoma cells. Further derivatization of the hydroxyl group with lipophilic groups to increase bioavailability improved their growth inhibitory properties for human glioblastoma and melanoma cells. In particular, the 4-bromobenzoyl derivative 26 demonstrated high efficacy for human tumor cells whereas primary human fibroblasts were less sensitive to 26. Therefore, functionalized pyrrolidines have the potential to inhibit the growth of tumor cells and display selectivity for tumor cells when compared to normal cells.

• Authors: Hélène Fiaux, Florence Popowycz, Sylvain Favre, Catherine Schütz, Pierre Vogel, Sandrine Gerber-Lemaire, Lucienne Juillerat-Jeanneret
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 13 Pg. 4237-46 (Jun 30 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15974577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Pyrrolidines
• alpha-Mannosidase

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Enzyme Inhibitors (chemistry, pharmacology)
• Glioblastoma (pathology)
• Humans
• Kinetics
• Melanoma (pathology)
• Models, Molecular
• Molecular Conformation
• Pyrrolidines (chemistry, pharmacology)
• Structure-Activity Relationship
• alpha-Mannosidase (antagonists & inhibitors)