OLIGONUCLEOTIDES WITH 3-HYDROXY-N-ACETYLPROLINOL AS SUGAR SUBSTITUTE

Fully modified oligonucleotides were synthesised from the 3-O-phosphor amidites of monomethoxytritylated droxy-N-[(N-6-benzoyladenin-9-yl)-ac etyl]-prolinol [(2S,3R) and (2R,3S) series], trans-3-hydroxy-N-[(thymi n-1-yl)-acetyl] [(2S,3R) and (2R,3S) series], and xy-N-[(N-6-benzoyl-a denin-9-yl)-acetyl]-L-prolinol (2R,3R). Remarkably, as well the L-tran s (2R,3S) as the D-trans (2S,3R) all-adenine oligonucleotides are capa ble of hybridisation with complementary DNA and RNA. With modified ail -thymine trans-oligomers no complexation with natural nucleic acids wa s observed. However, complex formation between two modified strands of the same sense of chirality does occur with formation of a triple str anded complex. The all-thymine oligonucleotides with trans-3-HO-N-acet ylprolinol backbone are capable of hybridisation with trans-4-HO-N-ace tylprolinol oligoadenylates of the same enantiomeric form in both the D and the L series, and inversely, the all-adenine oligonucleotide wit h the trans-3-HO conformation hybridises with the trans-4-HO oligothym idylates. While the former interactions have a triple stranded origin, the latter are 1:1 interactions. No interactions were noticed upon mi xing oligonucleotide analogues of different sense of chirality. Modifi ed mixed trans-3-HO A,T sequences display no hybridisation with comple mentary nucleic acids, nor homocomplex formation. The L-cis all-adenin e oligonucleotide hybridises with its RNA complement. Several complexe s were investigated by circular dichroism and microcalorimetry. In con clusion, the 3-hydroxy-N-acetylprolinol system represents an example o f homochiral oligonucleotides built up from two enantiomeric forms and hybridizing both with natural nucleic acids. (C) 1997 Elsevier Scienc e Ltd.