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

Abstract

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.

Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond

“…In 2008, Virta and Ketomäki published the solid-phase synthesis of conjugates of 30 and ribostamycin with 2'-O-methyl oligoribonucleotides by using conventional phosphoramidate chemistry (Scheme12). [54] For this purpose, appropriately protected aminoglycoside phosphoramidites,2 -cyanoethyl-…”

A Straightforward Preparation of Aminoglycoside–Dinucleotide and –diPNA Conjugates via Click Ligation Assisted by Microwaves

“…Aminoglycoside-oligonucleotide conjugates were known by forming thiourea, [6,12] amide, [7,[13][14] and phosphate [11] linkages, or by nucleobase derivatization. [15] We reasoned that CuAAC, the best known "click chemistry" transformation, [16] could also be a useful method for producing the ligation of aminoglycosides and oligonucleotides.…”

“…[10][11] Based on these reports, we were interested in further studying the properties of aminoglycoside-oligonucleotide conjugates as specific RNA ligands. Here, we report on a procedure for obtaining neomycin-or paromomycin-dinucleotide and -diPNA conjugates (Scheme 1) which combines copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC) with microwave irradiation (MW).…”

Amphiphilic Aminoglycosides as Medicinal Agents

“…In the antisense approach developed to target, for example, messager RNA sequences by hybridization and to inhibit the corresponding translation, conjugates of AGs (NEO, NEA, PARA, ribostamycin and methyl neobiosamine) to oligo-2′-deoxyribonucleotides (ODNs) were synthesized in order to allow the ODN cellular uptake [ 137 , 138 , 139 , 140 , 141 , 142 ]. However, in the resulting conjugates, the strong binding of AGs to the ODN through intramolecular charge–charge interaction between the protonated AG core and the phosphodiester backbone can disturb the selective binding to the RNA target.…”