title: α-D-mannose derivatives as models designed for selective inhibition of Golgi α-mannosidase II.
abstract: Human Golgi α-mannosidase II (hGM) is a pharmaceutical target for the design of inhibitors with anti-tumor activity. Nanomolar inhibitors of hGM exhibit unwanted co-inhibition of the human lysosomal α-mannosidase (hLM). Hence, improving specificity of the inhibitors directed toward hGM is desired in order to use them in cancer chemotherapy. We report on the rapid synthesis of D-mannose derivatives having one of the RS-, R(SO)- or R(SO(2))- groups at the α-anomeric position. Inhibitory properties of thirteen synthesized α-D-mannopyranosides were tested against the recombinant enzyme Drosophila melanogaster homolog of hGM (dGMIIb) and hLM (dLM408). Derivatives with the sulfonyl [R(SO(2))-] group exhibited inhibitory activities at the mM level toward both dGMIIb (IC(50) = 1.5-2.5 mM) and dLM408 (IC(50) = 1.0-2.0 mM). Among synthesized, only the benzylsulfonyl derivative showed selectivity toward dGMIIb. Its inhibitory activity was explained based on structural analysis of the built 3-D complexes of the enzyme with the docked compounds.
authors.affiliation: Institute of Chemistry, Center for Glycomics, GLYCOMED, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia. monika.polakova@savba.sk
authors.forename: Monika
authors.initials: M
authors.lastname: Poláková
authors.forename: Sergej
authors.initials: S
authors.lastname: Šesták
authors.forename: Erika
authors.initials: E
authors.lastname: Lattová
authors.forename: Ladislav
authors.initials: L
authors.lastname: Petruš
authors.forename: Ján
authors.initials: J
authors.lastname: Mucha
authors.forename: Igor
authors.initials: I
authors.lastname: Tvaroška
authors.forename: Juraj
authors.initials: J
authors.lastname: Kóňa
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008358:Mannose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008361:Mannosidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology; D043323:alpha-Mannosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013457:Sulfur Compounds; D008361:Mannosidases; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase; D043323:alpha-Mannosidase; D008358:Mannose