Pyrrolidine Derivatives as New Inhibitors of ?-Mannosidases and Growth Inhibitors of Human Cancer Cells

Abstract

New pyrrolidine-3,4-diol derivatives were prepared from D-(?)- and L-(+)-phenylglycinol and tested for their ability to inhibit 25 commercial glycosidases. The influence of the substitution of the lateral side chain and of the pyrrolidine ring on the enzyme inhibition was evaluated. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino} methyl)pyrrolidine-3,4-diol was a potent and selective inhibitor of ?-mannosidase from jack bean. This compound was derivatized into lipophilic esters in order to allow its internalization by human cancer cells. In particular, the 4-bromobenzoate derivative demonstrated promising inhibition of glioblastoma and melanoma cells whereas it was less effective on healthy human fibroblasts.