The properties of phosphodiester oligodeoxynucleotides (ODNs) containing 4′R-C-aminomethyl, -ethyl, -propyl, and -N-(2-aminoethyl)carbamoylthymidines (1, 2, 4, and 5) as potential antisense molecules are investigated in detail. We developed new radical chemistry with a vinylsilyl or an allylsilyl group as a temporary radical acceptor tether to synthesize the required 4′R-branched thymidines. Thus, an intramolecular radical cyclization of 4′-phenylseleno nucleosides 7a and 7b, which have a dimethylvinylsilyl and a dimethylallylsilyl group at the 3′-hydroxyl, respectively, with Bu 3 SnH/AIBN and subsequent Tamao oxidation (8b). Compounds 8a and 8b were then converted into 4′R-C-(2-trifluoroacetamidoethyl)thymidine 12a and 4′R-C-(3-trifluoroacetamidopropyl)thymidine 12b, which were phosphitylated to give the phosphoramidite units 14a and 14b. The phosphoramidite units of 1 and 5 were prepared by previous methods. The nucleosides 1, 2, 4, and 5 were incorporated into the 18-mer, 5′-d[MTMTMTMTMTMTMT-MTMT]-3′, where M is 5-methyl-2′-deoxycytidine, instead of T at various positions. We also prepared a 21-mer ODN 29 with a mixed sequence containing five residues of 2. The ODNs containing the modified nucleosides formed more stable duplexes with complementary DNA than the corresponding unmodified ODN. These ODNs also formed stable duplexes with the complimentary RNA. The ODNs containing the modified nucleosides were significantly resistant to nucleolytic hydrolysis by both snake venom phosphodiesterase (a 3′-exonuclease) and DNase I (an endonuclease) and were also very stable in PBS containing 50% human serum. It is worthwhile to note that these ODNs contain natural phosphodiester linkages. Furthermore, the duplexes formed by the ODNs containing the modified nucleosides and their complementary RNAs were good substrates for Escherichia coli RNase H and HeLa cell nuclear extracts as a source of human RNase H. Thus, these ODNs were identified as candidates for antisense molecules.

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