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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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Synthesis of compound 11. Experimental conditions: (a) BnONH2·HCl, EDAC, TEA, CH2Cl2, room temperature, 80%; (b) Boc2O, 4-(dimethylamino) pyridine, THF, room temperature, 96%; (c) PhSCl, AgOTf, 4 Å molecular sieves, 2,6-di-tert-butyl-4-methyl pyridine, CH2Cl2, 1R,2R-trans-cyclohexanediol in 1:1 THF − CH2Cl2, −78 °C to room temperature, 13%α-anomer and 60%β-anomer; (d) i. trimethylacetyl chloride, pyridine, triethylammoniun n-octadecyl hydrogenphosphonate, room temperature, ii. I2, pyridine (9.5 mL) – H2O (0.1 mL), room temperature, 58%; (e) i. 0.03 m NaOMe, MeOH, ii. Amberlite IR 120 (H+) resin, room temperature, 56%.
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fig03: Synthesis of compound 11. Experimental conditions: (a) BnONH2·HCl, EDAC, TEA, CH2Cl2, room temperature, 80%; (b) Boc2O, 4-(dimethylamino) pyridine, THF, room temperature, 96%; (c) PhSCl, AgOTf, 4 Å molecular sieves, 2,6-di-tert-butyl-4-methyl pyridine, CH2Cl2, 1R,2R-trans-cyclohexanediol in 1:1 THF − CH2Cl2, −78 °C to room temperature, 13%α-anomer and 60%β-anomer; (d) i. trimethylacetyl chloride, pyridine, triethylammoniun n-octadecyl hydrogenphosphonate, room temperature, ii. I2, pyridine (9.5 mL) – H2O (0.1 mL), room temperature, 58%; (e) i. 0.03 m NaOMe, MeOH, ii. Amberlite IR 120 (H+) resin, room temperature, 56%.

Mentions: The chemical synthesis of the glucocyclitol-phospholipid 11, Figure 3, began from the carboxylic acid 5 (26). An anomeric mixture of 5 was coupled to O-benzylhydroxylamine hydrochloride in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) to afford, after purification, the benzyloxyamide 6 which was treated with di-tert-butyl dicarbonate (Boc anhydride) and a catalytic amount of DMAP to give the N-Boc-protected hydroxamate 7. The introduction of the Boc protecting group was necessary in order to circumvent unwanted side reactions, which were apparent in previous studies, when activating the anomeric position for coupling to the cyclohexanediol moiety. The aforementioned coupling was achieved by converting the thioglycoside 7 to a glycosyl triflate through treatment with phenylsulfenyl triflate (PST) (31,32). PST was generated in situ by the addition of a freshly prepared solution of 0.4 m benzenesulfenyl chloride (29) to a solution of silver triflate (AgOTf) at −78 °C. After the addition of activated powdered 4 Å molecular sieves, a solution of the thioglycoside 7 and the proton scavenger DTBMP were added at −78 °C, followed by 1R,2R-trans-cyclohexanediol in THF − CH2Cl2 (1:1). Diligent RBC provided the α- and β-anomers 8 and 9, at 13% and 60% yields, respectively.


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)

Synthesis of compound 11. Experimental conditions: (a) BnONH2·HCl, EDAC, TEA, CH2Cl2, room temperature, 80%; (b) Boc2O, 4-(dimethylamino) pyridine, THF, room temperature, 96%; (c) PhSCl, AgOTf, 4 Å molecular sieves, 2,6-di-tert-butyl-4-methyl pyridine, CH2Cl2, 1R,2R-trans-cyclohexanediol in 1:1 THF − CH2Cl2, −78 °C to room temperature, 13%α-anomer and 60%β-anomer; (d) i. trimethylacetyl chloride, pyridine, triethylammoniun n-octadecyl hydrogenphosphonate, room temperature, ii. I2, pyridine (9.5 mL) – H2O (0.1 mL), room temperature, 58%; (e) i. 0.03 m NaOMe, MeOH, ii. Amberlite IR 120 (H+) resin, room temperature, 56%.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3473218&req=5

fig03: Synthesis of compound 11. Experimental conditions: (a) BnONH2·HCl, EDAC, TEA, CH2Cl2, room temperature, 80%; (b) Boc2O, 4-(dimethylamino) pyridine, THF, room temperature, 96%; (c) PhSCl, AgOTf, 4 Å molecular sieves, 2,6-di-tert-butyl-4-methyl pyridine, CH2Cl2, 1R,2R-trans-cyclohexanediol in 1:1 THF − CH2Cl2, −78 °C to room temperature, 13%α-anomer and 60%β-anomer; (d) i. trimethylacetyl chloride, pyridine, triethylammoniun n-octadecyl hydrogenphosphonate, room temperature, ii. I2, pyridine (9.5 mL) – H2O (0.1 mL), room temperature, 58%; (e) i. 0.03 m NaOMe, MeOH, ii. Amberlite IR 120 (H+) resin, room temperature, 56%.
Mentions: The chemical synthesis of the glucocyclitol-phospholipid 11, Figure 3, began from the carboxylic acid 5 (26). An anomeric mixture of 5 was coupled to O-benzylhydroxylamine hydrochloride in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) to afford, after purification, the benzyloxyamide 6 which was treated with di-tert-butyl dicarbonate (Boc anhydride) and a catalytic amount of DMAP to give the N-Boc-protected hydroxamate 7. The introduction of the Boc protecting group was necessary in order to circumvent unwanted side reactions, which were apparent in previous studies, when activating the anomeric position for coupling to the cyclohexanediol moiety. The aforementioned coupling was achieved by converting the thioglycoside 7 to a glycosyl triflate through treatment with phenylsulfenyl triflate (PST) (31,32). PST was generated in situ by the addition of a freshly prepared solution of 0.4 m benzenesulfenyl chloride (29) to a solution of silver triflate (AgOTf) at −78 °C. After the addition of activated powdered 4 Å molecular sieves, a solution of the thioglycoside 7 and the proton scavenger DTBMP were added at −78 °C, followed by 1R,2R-trans-cyclohexanediol in THF − CH2Cl2 (1:1). Diligent RBC provided the α- and β-anomers 8 and 9, at 13% and 60% yields, respectively.

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