Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.
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Enantiomeric C-6 fluorinated swainsonine derivatives as highly selective and potent inhibitors of α-mannosidase and α-l-rhamnosidase: Design, synthesis and structure-activity relationship study.
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The human Golgi α-mannosidase, hGMII, removes two mannose residues from GlcNAc-ManGlcNAc to produce GlcNAcManGlcNAc, the precursor of all complex -glycans including tumour-associated ones. The natural product GMII inhibitor, swainsonine, blocks processing of cancer-associated -glycans, but also inhibits the four other human α-mannosidases, rendering it unsuitable for clinical use. Our previous structure-guided screening of iminosugar pyrrolidine and piperidine fragments identified two micromolar hGMII inhibitors occupying the enzyme active pockets in adjacent, partially overlapping sites.
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Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address:
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Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 38 Bratislava, Slovakia. Electronic address:
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