ABSTRACT
AmpC ß-lactamase confers resistance to ß-lactam antibiotics in many Gram negative bacteria. Inducible expression of AmpC requires an N-acetylglucosaminidase termed NagZ. Here we describe the synthesis and characterization of hydroxyazepane inhibitors of NagZ. We find that these inhibitors enhance the susceptibility of clinically relevant Pseudomonas aeruginosa to ß-lactams.
Subject(s)
Acetylglucosaminidase/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Azepines/chemistry , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Pseudomonas aeruginosa/enzymology , beta-Lactams/chemistry , Acetylglucosaminidase/metabolism , Anti-Bacterial Agents/pharmacology , Azepines/pharmacology , Bacterial Proteins/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/pharmacology , Hydrogen Bonding , Pseudomonas aeruginosa/drug effects , beta-Lactamases/metabolism , beta-Lactams/pharmacologyABSTRACT
The mirror image of natural product (+)-adenophorine along with its 1-epi-, 1-homo-analogs and other derivatives have been synthesized and evaluated as glycosidase inhibitors. The synthetic strategy is based on the skeletal rearrangement of tetrahydroxylated C-alkyl azepanes obtained via a Staudinger/azaWittig/alkylation sequence starting from a sugar-derived azidolactol. Several organometallic species have been investigated for the alkylation step including organomagnesium, organolithium, organozinc, organoaluminum and organocerium reagents. While diallylzinc proved to be the most efficient to introduce an allyl substituent, disappointing results were obtained with the other organometallic species leading either to lower yields or no reaction. Enzymatic assays indicate that (-)-adenophorine is a moderate α-l-fucosidase inhibitor.
Subject(s)
Aza Compounds/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Glycoside Hydrolases/antagonists & inhibitors , Imino Sugars/chemistry , Alkylation , Animals , Aspergillus niger/enzymology , Aza Compounds/chemistry , Aza Compounds/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Glycoside Hydrolases/metabolism , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Oryza/enzymology , Protein Binding , Rats , Saccharomyces cerevisiae/enzymology , Stereoisomerism , alpha-L-Fucosidase/antagonists & inhibitors , alpha-L-Fucosidase/metabolismABSTRACT
A flexible synthetic access to six-membered L- and D-iminosugar C-glycosides is reported starting from the easily available 6-azido-6-deoxy-2,3,4-tri-O-benzyl-D-glucopyranose precursor. This methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a stereocontrolled ring contraction. It allows an efficient synthesis of iminosugar C-glycosides displaying structural diversity at both C-1 and C-6.
Subject(s)
Azides/chemistry , Glycosides/chemistry , Imino Sugars/chemistry , Lactones/chemistry , Alkylation , Azepines/chemistry , Isomerism , Molecular StructureABSTRACT
Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function. While stable D-gluco-like analogs have been reported, no data are available for D-manno-like structures. A series of tri- and tetrahydroxylated seven-membered iminosugars displaying either a D-manno-or a L-gulo-like configuration, were synthesized from methyl α-D-mannopyranoside using a reductive amination-mediated ring expansion as the key step. Screening towards a range of commercial glycosidases demonstrated their potency as competitive glycosidase inhibitors while cellular assay showed selective albeit weak glycoprotein processing mannosidase inactivation.
Subject(s)
Azepines/chemistry , Enzyme Inhibitors/chemical synthesis , Glucosamine/analogs & derivatives , Glycoside Hydrolases/antagonists & inhibitors , Mannose/chemistry , Azepines/chemical synthesis , Enzyme Inhibitors/chemistry , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glycoside Hydrolases/metabolism , HydroxylationABSTRACT
Regiospecific synthesis of title compounds is based either on cycloaddition of ketene acetals derived from Hagemann's ester or of homophthalic anhydrides. Thus, tetracenomycin D and 3,8-di-O-methyl saintopin have been prepared in few steps. New derivatives of 10-deoxysaintopin have been also obtained. Evaluation of their cytotoxicity against L1210 leukemia cells are reported.