alpha-D-Mannose derivatives as models designed for selective inhibition of Golgi alpha-mannosidase II

作者：Polakova Monika^*; Sestak Sergej; Lattova Erika; Petrus Ladislav; Mucha Jan; Tvaroska Igor; Kona Juraj

来源：European Journal of Medicinal Chemistry, 2011, 46(3): 944-952.

DOI：10.1016/j.ejmech.2011.01.012

• Synthetic alpha-D-mannopyranosides
• Oxidation
• Mannopyranosyl sulfones
• Mannopyranosyl sulfoxides
• alpha-Mannosidase inhibitors
• Molecular modeling

Human Golgi alpha-mannosidase II (hGM) is a pharmaceutical target for the design of inhibitors with antitumor activity. Nanomolar inhibitors of hGM exhibit unwanted co-inhibition of the human lysosomal alpha-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 alpha-anomeric position. Inhibitory properties of thirteen synthesized alpha-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.

• 出版日期2011-3