2-deoxystreptamine Derivatives Research Articles

Mutations in Gene fusA1 as a Novel Mechanism of Aminoglycoside Resistance in Clinical Strains of Pseudomonas aeruginosa.

Resistance of clinical strains of Pseudomonas aeruginosa to aminoglycosides can result from production of transferable aminoglycoside-modifying enzymes, of 16S rRNA methylases, and/or mutational derepression of intrinsic multidrug efflux pump MexXY(OprM). We report here the characterization of a new type of mutant that is 4- to 8-fold more resistant to 2-deoxystreptamine derivatives (e.g., gentamicin, amikacin, and tobramycin) than the wild-type strain PAO1. The genetic alterations of three in vitro mutants were mapped on fusA1 and found to result in single amino acid substitutions in domains II, III, and V of elongation factor G (EF-G1A), a key component of translational machinery. Transfer of the mutated fusA1 alleles into PAO1 reproduced the resistance phenotype. Interestingly, fusA1 mutants with other amino acid changes in domains G, IV, and V of EF-G1A were identified among clinical strains with decreased susceptibility to aminoglycosides. Allelic-exchange experiments confirmed the relevance of these latter mutations and of three other previously reported alterations located in domains G and IV. Pump MexXY(OprM) partly contributed to the resistance conferred by the mutated EF-G1A variants and had additive effects on aminoglycoside MICs when mutationally upregulated. Altogether, our data demonstrate that cystic fibrosis (CF) and non-CF strains of P. aeruginosa can acquire a therapeutically significant resistance to important aminoglycosides via a new mechanism involving mutations in elongation factor EF-G1A.

2′-Modified Neamine Analogues from Thiomannosides through Glycosidation-Stereoinversion

Conveniently protected neamine analogues were synthesized with a free 2′-OH group for further functionalization. An approach was investigated involving a stereoselective α-glycosidation reaction of 3,4-O-dimethoxybutanediyl-2-O-silyl protected thiomannosides with a 2-deoxystreptamine derivative. Subsequent 2-O-deprotection followed by anoxidation–reduction sequence led to α-glucosides withstereoinversion at C-2′. The scope of the procedure for the syntheses of α-glucosides was explored with three distinct model acceptors. Thiomannoside coupling, 2-O-deprotection, and oxidation were straightforward, whereas the outcome of the reduction step was clearly acceptor-dependent.

Fully Orthogonally Protected 2-Deoxystreptamine from Kanamycin

A fully orthogonally protected and enantiopure 2-deoxystreptamine derivative is prepared in a few straightforward steps from commercially available kanamycin. Resolution of a sterically hindered diacetate was effected by a Verenium esterase and was followed by a chemoselective Staudinger reduction-acylation protocol.

Self-assembled lamellar complexes of siRNA with lipidic aminoglycoside derivatives promote efficient siRNA delivery and interference

RNA interference requires efficient delivery of small double-stranded RNA molecules into the target cells and their subsequent incorporation into RNA-induced silencing complexes. Although current cationic lipids commonly used for DNA transfection have also been used for siRNA transfection, a clear need still exists for better siRNA delivery to improve the gene silencing efficiency. We synthesized a series of cationic lipids characterized by head groups bearing various aminoglycosides for specific interaction with RNA. siRNA complexation with such lipidic aminoglycoside derivatives exhibited three lipid/siRNA ratio-dependent domains of colloidal stability. Fluorescence and dynamic light-scattering experiments showed that cationic lipid/siRNA complexes were formed at lower charge ratios, exhibited a reduced zone of colloidal instability, and had smaller mean diameters compared with our previously described guanidinium-based cationic lipids. Cryo-transmission electron microscopy and x-ray-scattering experiments showed that, although the final in toto morphology of the lipid/siRNA complexes depended on the aminoglycoside type, there was a general supramolecular arrangement consisting of ordered lamellar domains with an even spacing of 67 A. The most active cationic lipid/siRNA complexes for gene silencing were obtained with 4,5-disubstituted 2-deoxystreptamine aminoglycoside derivatives and were characterized by the siRNA being entrapped in small particles exhibiting lamellar microdomains corresponding to siRNA molecules sandwiched between the lipid bilayers. These results clearly show that lipidic aminoglycoside derivatives constitute a versatile class of siRNA nanocarriers allowing efficient gene silencing.

Preparation of 2-deoxystreptamine derivatives with all-axial substituents for desymmetrization

2-Deoxystreptamine derivatives with all-axial substituents were prepared with new methods. They are potential compounds for desymmetrization.

Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.

The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.

Synthesis of a protected enantiomerically pure 2-deoxystreptamine derivative from d-allylglycine

A diastereoselective synthetic route from d-allylglycine to the enantiopure (protected) 2-deoxystreptamine derivative 14 is presented. Key steps involve two consecutive chain extensions––with crucial stereodirective roles for the amino protective groups, ring closure by olefin metathesis, face selective dihydroxylation, cyclic sulfate formation and finally opening with azide. The resulting 2-deoxystreptamine derivative is ideally protected for the preparation of 4,5- or 4,6-linked aminoglycoside antibiotics.

Efficient Synthesis of Heterocyclic 2-Deoxysteptamine Derivatives as RNA Binding Ligands

Abstract An efficient strategy for the synthesis of heterocyclic 2-deoxystreptamine derivatives is described. The resulting compounds showed good RNA binding affinities from ESI-MS RNA binding assay.

An efficient synthesis of mimetics of neamine for RNA recognition.

As mimetics of neamine, several 4-heterocyclic 2-deoxystreptamine derivatives were chemically synthesized for RNA recognition. Conversion of 4-methylthiomethyl-5,6-di-O-acetyl-diazido-2-deoxystreptamine to the 4-chloromethyl derivative followed by reactions with different nuclophilic reagents gave the 4-heterocyclic 2-deoxystreptamine derivatives in satisfactory yields.

ChemInform Abstract: Synthesis of Apramycin Analogues.

Abstract The synthesis is described of a pseudotrisaccharide analogue of apramycin from a suitably protected 2-deoxystreptamine derivative by the stepwise application of the BF 3 -catalysed addition of alcohols to glycals.

Synthesis of apramycin analogues

The synthesis is described of a pseudotrisaccharide analogue of apramycin from a suitably protected 2-deoxystreptamine derivative by the stepwise application of the BF 3-catalysed addition of alcohols to glycals.

ChemInform Abstract: A SYNTHESIS OF NEAMINE

AbstractKondensation des α‐D‐Glucopyranosylbromides (I) mit dem Streptamin‐Derivat (i)‐(II) und Behandlung des gebildeten Produktes erst mit H2SO4 und dann mit Chlorameisensäureethylester gibt die isomeren Glucoside (IIIa) und (IVa) [Glucosidierung von (I) mit (i)‐(II)‐Analogen, deren N‐Schutzgruppe Benzyloxycarbonyl oder Allyloxycarbonyl ist, verläuft nicht so günstig wie mit (i)‐(II) deren Gemisch mit NaN3 zu den isomeren Aziden (IIIb) und (IVb) reagiert.

A Synthesis of Neamine

Abstract Neamine and its position isomer were synthesized from 3,4-di-O-acetyl-2-deoxy-2-(p-methoxybenzylidene-amino)-6-O-tosyl-α-d-glucopyranosyl bromide and racemic 5,6(4,5)-O-cyclohexylidene-2-deoxy-1,3-bis-N-(ethoxycarbonyl) streptamine. Influence of the N-protecting groups of 2-deoxystreptamine derivatives for glycosylation was discussed. The unusual Δ[M]TACu value of the position isomer of neamine was ascribed to the interaction between the 6′-amino group and other groups.

Aminocyclitols. 36. Chlorination and Dechlorination of Aminocyclitol and Inositol Derivatives. Preparation of Dideoxy-and Trideoxystreptamines

Abstract Chlorination of four aminocyclitol and six inositol derivatives with sulfuryl chloride gave the chloro substitution products, which were then dechlorinated by hydrogenolysis with Raney nickel or by treatment with tributyltin(IV) hydride giving the corresponding deoxy compounds. Several useful aminocyclitols, including 2,4-dideoxy- and 2,4,5-trideoxystreptamines, were prepared from 2-deoxystreptamine derivatives by these procedures.

Synthetic studies on carbohydrate antibiotics. XIV. Syntheses of neamine and its diastereomer; the condensation of protected 2,6-diamino-2,6-dideoxy-.ALPHA.-D-glucopyranosyl bromide with a 2-deoxystreptamine derivative.

3,4-Di-O-acetyl-2,6-dideoxy-2-(2′,4′-dinitroanilino)-6-phthalimido-α-d-glucopyranosyl bromide (I) was prepared in a good yield from glucosamine hydrochloride. A modified Konigs-Knorr condensation of this bromide with a 2-deoxysteptamine derivative afforded a neamine derivative (IX) and its diastereomer (X). These compounds, (IX) and (X), were identified by PMR spectroscopy after conversion into the corresponding N-acetyl derivatives, (XI) and (XII).

The gentamicin antibiotics. 3. The gross structures of the gentamicin C components.

Methanolysis of the gentamicin C components gave methyl garosaminide and the corresponding gentamines, isolated as crystalline tetra-N-acetates. The absolute stereochemistry of the 2-deoxystreptamine portion of these tetra-N-acetates was determined by a circular dichroism method. Methylation of the penta-N-acetylgentamicin C components followed by acid hydrolysis and reacetylation gave, in each case, NN′-diacetyl-2-deoxy-NN′,5-O-tri-methylstreptamine, establishing the gentamicins to be 4,6-disubstituted 2-deoxystreptamine derivatives.

2-Deoxystreptamine Derivatives

A group of N- and O-substituted 2-deoxystreptamine derivatives and their salts, represented by types I and II, have been synthesized for biological evaluation. Methods of their syntheses are discussed.