Synthesis and evaluation of dimeric lipophilic iminosugars as inhibitors of glucosylceramide metabolism

Four dimeric and four monomeric lipophilic iminosugars were synthesized and subsequently evaluated on their inhibitory potential towards mammalian glucosylceramide synthase, glucocerebrosidase, β-glucosidase 2, sucrase and lysosomal α-glucosidase. Compared to their monomeric counterparts the dimeric inhibitors showed decreased inhibition of glucosylceramide synthase and generally a comparable inhibitory potency for the glycosidases.

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N,N′-{5,5′-[2-(Adamantan-1-yl)propane-1,3-diyl]bis(oxy)bis(pentane-5,1-diyl)}-bis(2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin)C91H112N2O10[α]D20=-2.4 (c 3.7 CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5R)

N,N′-{5,5′-[2-(Adamantan-1-yl)propane-1,3-diyl]bis(oxy)bis(pentane-5,1-diyl)}-bis(2,3,4,6-tetra-O-benzyl-l-ido-1-deoxynojirimycin)C91H112N2O10[α]D20=-21.8 (c 1.8 CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5S)

N,N′-{5,5′-[Adamantan-1,3-diylbis(methylene)]bis(oxy)bis(pentane-5,1-diyl)}-bis(2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin)C90H110N2O10[α]D20=-3.0 (c 2.4 CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5R)

N,N′-{5,5′-[Adamantan-1,3-diylbis(methylene)]bis(oxy)bis(pentane-5,1-diyl)}-bis(2,3,4,6-tetra-O-benzyl-l-ido-1-deoxynojirimycin)C90H110N2O10[α]D20=-25.9 (c 2.1 CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5S)

N,N′-{5,5′-[2-(Adamantan-1-yl)propane-1,3-diyl]bis(oxy)bis(pentane-5,1-diyl)}-bis(1-deoxynojirimycin)C35H64N2O10[α]D20=-8.8 (c 1.9 MeOH)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5R)

N,N′-{5,5′-[2-(Adamantan-1-yl)propane-1,3-diyl]bis(oxy)bis(pentane-5,1-diyl)}-bis(l-ido-1-deoxynojirimycin)C35H64N2O10[α]D20=+11.4 (c 2.6 MeOH)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5S)

N,N′-{5,5′-[Adamantan-1,3-diylbis(methylene)]bis(oxy)bis(pentane-5,1-diyl)}-bis(1-deoxynojirimycin)C34H62N2O10[α]D20=-3.6 (c 3.6 MeOH)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5R)

N,N′-{5,5′-[Adamantan-1,3-diylbis(methylene)]bis(oxy)bis(pentane-5,1-diyl)}-bis(l-ido-1-deoxynojirimycin)C34H62N2O10[α]D20=+13.2 (c 3.1 MeOH)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5S)

N-[5-(Adamantan-1-yl-ethoxy)-pentyl]-1-deoxynojirimycinC23H41NO5[α]D20=-16.6 (c 0.8 MeOH)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5R)

N-[5-(Adamantan-1-yl-ethoxy)-pentyl]-l-ido-1-deoxynojirimycinC23H41NO5[α]D20=+11.9 (c 0.8 MeOH)Source of chirality: d-glucoseAbsolute configuration: (2S,3R,4R,5S)