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Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness.

Abdelwahab NZ, Crossman AT, Sullivan L, Ferguson MA, Urbaniak MD - Chem Biol Drug Des (2012)

Bottom Line: We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups.Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme.Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC(50) values 0.1-1.5mM and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the α1-4-mannose transferase with an apparent IC(50)= 19±0.5μm.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.

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Structures of the deoxy-2-C-branched monosaccharides.
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fig02: Structures of the deoxy-2-C-branched monosaccharides.

Mentions: We have postulated that ZBGs could act as inhibitors of the T. brucei GlcNAc-PI de-N-acetylase (22). As part of our efforts to test this hypothesis, we have previously reported the synthesis of a GlcNAc-PI analog incorporating an N-hydroxyurea zinc-binding moiety (1-d-6-O-[2-(N-hydroxyaminocarbonyl)amino-2-deoxy-α-d-glucopyranosyl]-myo-inositol 1-(n-octadecyl phosphate) (25). Unfortunately, this compound proved to be unstable under the conditions employed in the activity assay and was therefore judged to be unsuitable for further study. We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides incorporating ZBGs, Figure 2 (26). Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a ZBG and report the biological evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome GlcNAc-PI de-N-acetylase.


Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness.

Abdelwahab NZ, Crossman AT, Sullivan L, Ferguson MA, Urbaniak MD - Chem Biol Drug Des (2012)

Structures of the deoxy-2-C-branched monosaccharides.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473218&req=5

fig02: Structures of the deoxy-2-C-branched monosaccharides.
Mentions: We have postulated that ZBGs could act as inhibitors of the T. brucei GlcNAc-PI de-N-acetylase (22). As part of our efforts to test this hypothesis, we have previously reported the synthesis of a GlcNAc-PI analog incorporating an N-hydroxyurea zinc-binding moiety (1-d-6-O-[2-(N-hydroxyaminocarbonyl)amino-2-deoxy-α-d-glucopyranosyl]-myo-inositol 1-(n-octadecyl phosphate) (25). Unfortunately, this compound proved to be unstable under the conditions employed in the activity assay and was therefore judged to be unsuitable for further study. We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides incorporating ZBGs, Figure 2 (26). Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a ZBG and report the biological evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome GlcNAc-PI de-N-acetylase.

Bottom Line: We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups.Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme.Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC(50) values 0.1-1.5mM and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the α1-4-mannose transferase with an apparent IC(50)= 19±0.5μm.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.

Show MeSH
Related in: MedlinePlus