Hydrolysis of an RNA dinucleoside monophosphate by neomycin B

Kirk, Sarah R.; Tor, Yitzhak

doi:10.1039/a706023h

Cited by 17 publications

(21 citation statements)

References 24 publications

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“…The residue was purified via silica gel chromatography (4% MeOH in CH 2 Cl 2 ) to yield 0.21 g (97%) of the product (24) 1,3,2′,6′-Tetraazido-5″-O-(4-methoxytrityl)ribostamycin (26). 6,3′,4′, 2″, 3″, 5″-Hexa-O-acetyl-1,3,2′,6′-tetraazidoribostamycin (23) (35) was first synthesized from the neamine derivative (19). 19 (0.30 g, 0.54 mmol) and 1,2,3,5-tetra-O-acetyl--D-ribofuranose (0.35 g, 1.1 mmol) were dissolved in dry dichloromethane (2.0 mL).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of Aminoglycoside Conjugates of 2′-O-Methyl Oligoribonucleotides

Ketomäki

Virta

2008

Bioconjugate Chem.

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Aminoglycoside conjugates of 2'- O-methyl oligoribonucleotides have been synthesized entirely on a solid phase using conventional phosphoramidate chemistry. For this purpose, appropriately protected neamine-derived phosphoramidites, viz., 2-cyanoethyl [6,3',4'-tri- O-levulinoyl- N (1), N (3), N (2) (') , N (6) (') -tetra(trifluoroacetyl)neamine-5- O-ethyl] N,N-diisopropylphosphoramidite, 1, and 2-cyanoethyl [6,3',4',2'',3''-penta- O-levulinoyl- N (1), N (3), N (2) (') , N (6) (') -tetra(trifluoroacetyl) ribostamycin-5''-yl] N, N-diisopropylphosphoramidite, 2, have been prepared and attached via phosphodiester linkage to an appropriate 2'- O-methyl oligoribonucleotide. Levulinoyl esters are used to cap the hydroxyl groups of the aminoglycoside moieties, since they may be selectively removed prior to ammonolysis. In this manner, the potential O-->N acyl migration is excluded. Applicability of the strategy has been demonstrated by the synthesis of eight different aminoglycoside conjugates, in which 1 and 2 are attached directly to the 5'-end ( 6 and 10) or, alternatively, to an inserted non-nucleosidic hydroxyalkyl armed branching unit ( 3, 4, or 5), which results in intrachain conjugates ( 7- 9, 11- 13). The potential of these conjugates to act as a sequence-selective artificial nuclease has been studied.

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Section: Methodsmentioning

confidence: 99%

“…The azide masked neamine (19) was a useful starting material also for the ribostamycin derived phosphoramidite (2). The 5-OH of protected neamines is usually only weakly reactive, like in acylations ( cf.…”

Section: Synthesis Of the Aminoglycosidementioning

confidence: 99%

Synthesis of Aminoglycoside Conjugates of 2′-O-Methyl Oligoribonucleotides

Ketomäki

Virta

2008

Bioconjugate Chem.

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“…They have been found to promote the cleavage of hairpin ribozymes, to indirectly interfere with the splicing of the td intron, to act as enhancers of the catalytic properties of group I intron ribozymes, and even to inhibit ribozymes such as the hammerhead and hepatitis delta virus (HDV) ribozymes [21]. Neomycin B has also been reported to catalyze phosphodiester hydrolysis in a model RNA system, adenylyl(3′-5′)adenosine (ApA) [29], and RNA oligonucleotides [30]. However, in order for the aminoglycosides to reach these and other intracellular targets they must first penetrate the cell membrane.…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 99%

Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D)

Joshi

Voo

Graham

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The rapid increase in multi-drug resistant bacteria has resulted in previously discontinued treatments being revisited. Aminoglycosides are effective "old" antibacterial agents that fall within this category. Despite extensive usage and understanding of their intracellular targets, there is limited mechanistic knowledge regarding how aminoglycosides penetrate bacterial membranes. Thus, the activity of two well-known aminoglycosides, kanamycin A and neomycin B, towards a bacterial mimetic membrane (DMPC:DMPG (4:1)) was examined using a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). The macroscopic effect of increasing the aminoglycoside concentration showed that kanamycin A exerts a threshold response, switching from binding to the membrane to disruption of the surface. Neomycin B, however, disrupted the membrane at all concentrations examined. At concentrations above the threshold value observed for kanamycin A, both aminoglycosides revealed similar mechanistic details. That is, they both inserted into the bacterial mimetic lipid bilayer, prior to disruption via loss of materials, presumably aminoglycoside-membrane composites. Depth profile analysis of this membrane interaction was achieved using the overtones of the quartz crystal sensor. The measured data is consistent with a two-stage process in which insertion of the aminoglycoside precedes the 'detergent-like' removal of membranes from the sensor. The results of this study contribute to the insight required for aminoglycosides to be reconsidered as active antimicrobial agents/co-agents by providing details of activity at the bacterial membrane. Kanamycin and neomycin still offer potential as antimicrobial therapeutics for the future and the QCM-D method illustrates great promise for screening new antibacterial or antiviral drug candidates.

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“…[36] Aminoglycoside-specific RNA aptamers have been selected in vitro, [37] and NMR studies have revealed the structures of the complexes with their cognate aminoglycosides.…”

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confidence: 99%

RNA and the Small Molecule World

Tor

1999

Angew. Chem. Int. Ed.

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A key role in essential cellular processes is played by RNA molecules, and these are attractive targets for drug design. The functional diversity of RNA can be attributed to the sophisticated three-dimensional structures it assumes. These intricate folds create potential binding pockets for ions, low molecular weight ligands, and proteins. Recent experiments have demonstrated that small molecules such as tobramycin (1) can regulate gene expression in living cells through specific interactions with a messenger RNA (mRNA).

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Hydrolysis of an RNA dinucleoside monophosphate by neomycin B

Cited by 17 publications

References 24 publications

Synthesis of Aminoglycoside Conjugates of 2′-O-Methyl Oligoribonucleotides

Synthesis of Aminoglycoside Conjugates of 2′-O-Methyl Oligoribonucleotides

Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D)

RNA and the Small Molecule World

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