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(SO2)- 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(SO2)-] group exhibited inhibitory activities at the mM level toward both dGMIIb (IC50=1.5–2.5mM) and dLM408 (IC50=1.0–2.0mM). 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.