An Extended Phosphate Linkage: Synthesis,Hybridization and Modeling Studies of Modified Oligonucleotides |
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Authors: | Becky Haly Laurent Bellon † Venkatraman Mohan Yogesh Sanghvi |
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Affiliation: | Medicinal Chemistry Department , Isis Pharmaceuticals , 2292 Faraday Avenue, Carlsbad, CA, 92008 |
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Abstract: | Abstract Novel stretched oligonucleotides (A-D) containing a 3′-α-C-methylene phosphodiester bridge (5-atoms long) have been synthesized on an automated synthesizer utilizing phosphoramidite chemistry. The key building-block 1-[3′-O-β-cyanoethyldiisopropylaminophosphiryl-2,3-dideoxy-5-O-dimethoxytriphenylmethyl-3-C-(hydroxymethyl)-β-D-erythro-pentofuranosyl]thymine (21) was prepared in a stereoselective manner from thymidine. Hybridization studies indicated a drop (1.8–3.0°C/mod.) in affinity for the complementary RNA and DNA targets. Molecular modeling results indicated that the 5-atom modified backbone had a different geometry around the phosphodiester linkage compared to the natural phosphodiester linkage. The stretched backbone may not be useful for antisense or triplex constructs, however it may find applications in biochemical/enzyme studies. |
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