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α-D-mannose derivatives as models designed for selective inhibition of Golgi α-mannosidase II.

European journal of medicinal chemistry (2011-02-08)
Monika Poláková, Sergej Šesták, Erika Lattová, Ladislav Petruš, Ján Mucha, Igor Tvaroška, Juraj Kóňa
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
D-(+)-Mannose, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
D-(+)-Mannose, BioUltra, ≥99.5% (sum of enantiomers, HPLC)
Millipore
D-(+)-Mannose, suitable for microbiology, ≥99%
Millipore
D-(+)-Mannose, ≥99.0% (sum of enantiomers, HPLC), suitable for microbiology
Sigma-Aldrich
D-(+)-Mannose, wood, ≥99%