| Abstract
| - A versatile synthetic route has been developed for the synthesis of 2‘-O-[2-[(N,N-dimethylamino)oxy]ethyl] (abbreviated as 2‘-O-DMAOE) modified purine and pyrimidine nucleosides and theircorresponding nucleoside phosphoramidites and solid supports. To synthesize 2‘-O-DMAOE purinenucleosides, the key intermediate B (Scheme ) was obtained from the 2‘-O-allyl purine nucleosides(13a and 15) via oxidative cleavage of the carbon−carbon bond to the corresponding aldehydesfollowed by reduction. To synthesize pyrimidine nucleosides, opening the 2,2‘-anhydro-5-methyluridine 5 with the borate ester of ethylene glycol gave the key intermediate B. The 2‘-O-(2-hydroxyethyl) nucleosides were converted, in excellent yield, by a regioselective Mitsunobu reaction,to the corresponding 2‘-O-[2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]ethyl] nucleosides (18, 19,and 20). These compounds were subsequently deprotected and converted into the 2‘-O-[2-[(methyleneamino)oxy]ethyl] derivatives (22, 23, and 24). Reduction and a second reductiveamination with formaldehyde yielded the corresponding 2‘-O-[2-[(N,N-dimethylamino)oxy]ethyl]nucleosides (25, 26, and 27). These nucleosides were converted to their 3‘-O-phosphoramidites andcontrolled-pore glass solid supports in excellent overall yield. Using these monomers, modifiedoligonucleotides containing pyrimidine and purine bases were synthesized with phosphodiester,phosphorothioate, and both linkages (phosphorothioate and phosphodiester) present in the sameoligonucleotide as a chimera in high yields. The oligonucleotides were characterized by HPLC,capillary gel electrophoresis, and ESMS. The effect of this modification on the affinity of theoligonucleotides for complementary RNA and on nuclease stability was evaluated. The 2‘-O-DMAOEmodification enhanced the binding affinity of the oligonucleotides for the complementary RNA (andnot for DNA). The modified oligonucleotides that possessed the phosphodiester backbone demonstrated excellent resistance to nuclease with t1/2> 24 h.
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