bekanamycin and neamine

This work describes chiral phosphoric acid (CPA)-catalyzed desymmetrizative glycosylation of meso-diol derived from 2-deoxystreptamine. The chirality of CPA dictates the outcome of the glycosylation reactions, and the use of enantiomeric CPAs results in either C4-glycosylated (67 : 33 d.r.) or C6-glycosylated (86 : 14 d.r.) 2-deoxystreptamines. These glycosylated products can be converted to aminoglycosides, and the application of this strategy to the synthesis of protected iso-neamine and iso-kanamycin B with inverted connection at the C4 and C6 positions is described.

Topics: Aminoglycosides; Catalysis; Framycetin; Glycosylation; Hexosamines; Kanamycin; Phosphoric Acids; Stereoisomerism

We studied six pairs of aminoglycosides and their corresponding ribosylated derivatives synthesized by attaching a β-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudo-oligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to cytosolic eukaryotic in vitro translation. For the pseudodisaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivatives were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. On the basis of the results of this study, we suggest that modification of the 5-OH position of the streptamine ring of other natural or semisynthetic pseudodisaccharide aminoglycoside scaffolds containing an equatorial amine at the 2' sugar position with a β-O-linked ribofuranose is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity.

Topics: Aminoglycosides; Anti-Bacterial Agents; Escherichia coli Proteins; Framycetin; Gram-Negative Bacteria; Kanamycin; Microbial Sensitivity Tests; Ribose; Structure-Activity Relationship; Trisaccharides

Aminoglycosides are a family of molecules based on a 2-deoxystreptamine ring that is functionalized with a variety of sugar units that contain vicinal amine and hydroxyl functionality. These positively-charged amines promote selective high affinity binding to bacterial 16 s rRNA with resultant antibacterial activity. Aminoglycosides have also been shown to selectively target a variety of therapeutically relevant RNA motifs, and in combination with copper to promote irreversible degradation of the RNA target. The presence of multiple hydroxyl and amine groups on multiple rings creates many potential copper coordination sites. However, only a small subset of these sites actually bind copper, which have not been clearly defined experimentally, Herein we describe a more extensive structural characterization of the complexes of six aminoglycosides (kanamycin A, kanamycin B, neomycin B, neamine, tobramycin and paromomycin) that provide insights on the factors contributing to the coordination selectivity of aminoglycosides toward divalent copper. The presence of vicinal ligand donors capable of chelating the copper ion appears to be a prerequisite for stable metal binding, with charge density providing further tuning of the K(D). A possible role for metal coordination in antibacterial activity is also considered.

Topics: Aminoglycosides; Anti-Bacterial Agents; Binding Sites; Copper; Framycetin; Kanamycin; Magnetic Resonance Spectroscopy; Molecular Structure; Paromomycin; Spectrophotometry, Ultraviolet; Static Electricity; Tobramycin