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.