Selective Trihydroxylated Azepane Inhibitors of NagZ, a Glycosidase Involved in Pseudomonas Aeruginosa Resistance to β-lactam Antibiotics

The synthesis of a series of D-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B. The synthesis of a series of D-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B &nbsp

(2S,3R,4R,5S)-3,4-O-isopropylidene-2-methyl-1-oxa-6,9-diazaspiro[4.5]decane-7,10-dione

The synthesis of (2S,3R,4R,5S)-3,4-O-Isopropylidene-2-methyl-1-oxa-6,9- diazaspiro[4.5]decane -7,10-dione was investigated. The organic compound, C 11H13N2O5, was prepared from L-fucose in a sequence that produced this compound and an anomer. The crystal structure determination removed ambiguities in the synthetic sequence. The results show that the overall geometry is essentially same in the ordered and the disordered molecules and is unexceptional

6C-butylglucoses from glucuronolactone: Suppression of silyl migration during borohydride reduction of lactols by cerium (III) chloride: Inhibition of phosphoglucomutase

The synthesis of the epimeric 6C-butylglucoses from D-glucuronolactone is reported. The sodium borohydride reduction of two fully protected lactols is highly stereoselective but is accompanied by migration of a silyl protecting group; in the presence of cerium(III) chloride, there is little change in the stereoselectivity but the migration of the silyl group is suppressed. 6R-6C-Methylglucose and 6R-6C-butlylglucose are both better inhibitors of phosphoglucomutase than their 6S epimers

Sugar amino acids at the anomeric position of carbohydrates: synthesis of spirocyclic amino acids of 6-deoxy-L-lyxofuranose

Two anomeric spirodiketopiperazines and one spirohydantoin of 6-deoxy-l-lyxofuranose have been prepared from l-fucono-δ-lactone via ring contraction to the corresponding tetrahydrofuran carboxylate and anomeric functionalization including regioselective bromination and azide displacement. © 2006 Elsevier Ltd. All rights reserved

Tetrahydrofuran alpha-azido esters: Precursors of anomeric alpha-amino acid monomers via radical bromination

A general route for the synthesis of tetrahydrofuran α-azido esters as the equivalent of monomeric furanose anomeric α-amino acids is described. Highly selective radical bromination of a range of suitably protected carbohydrate C-glycosyl derivatives affords bromo-esters which undergo efficient displacement by azide to give anomeric α-amino acid derivatives

New 1-amino-1-deoxy- and 2-amino-2-deoxy-polyhydroxyazepanes: synthesis and inhibition of glycosidases

Eight new seven-membered ring iminoalditols, displaying an amino group and a hydroxymethyl group on the ring, have been synthesized from D-arabinose via epoxidation of a protected azacycloheptene and subsequent nucleophilic opening. Three of them show a potent glycosidase inhibition on amyloglucosidase and, to a lesser extend, on alpha-L-fucosidase. (C) 2004 Elsevier Ltd. All rights reserved

Synthesis of seven- and eight-membered carbasugar analogs via ring-closing metathesis and their inhibitory activities toward glycosidases

An expeditious and efficient synthesis of new enantiopure polyhydroxylated seven- and eight-membered carbocycles is described starting from 2,3.5-tri-O-benzyl-D-arabinose. The key cyclization step involves ring closing metathesis of 1,8- and 1,9-dienes using Grubbs' catalyst. All of the new carbasugar analogs synthesized were evaluated as glycosidase inhibitors. Contrary to Our expectations, (1 S,2S,3R,4R,5R)-1-(hydroxymethyl)-cyclohepta-1,2,3,4,5-pentol which has the beta-D-mannopyranose configuration for C(1)-C(5) inhibits alpha- and beta-glucosidases, whereas its diepimer (1S,2S,3R,4S,5S)-1-(hydroxymethyl)-cyclohepta-1,2,3,4,5-pentol, which has the alpha-D-glucopyranose configuration, is not recognised by these enzymes. (C) 2002 Elsevier Science Ltd. All rights reserved