Oligonucleotides with (N-thymin-1-ylacetyl)-1-arylserinol backbone: chiral acyclic analogs with restricted conformational flexibility

Abstract

All four threo/erythro stereoisomers of 2(R/S)-(N-thymin-1-ylacetyl)-amino-1(R/S)-aryl-1,3-propanediol were synthesized from 2(R/S)-amino-1(R/S)-aryl-1,3-propanediol in 45-50% overall yield. The inversion of the C1 hydroxyl group in (1S, 2S), 4a, and (1R, 2R), 4d, was accomplished under Mitsunobu conditions to get (1R, 2S), 4c, and (1S, 2R), 4e isomers, respectively. Compounds 4a-f were individually converted into their respective amidite synthons 5a-f. All these stereoisomers were individually incorporated into oligonucleotides (ODNs) at pre-determined positions and various biophysical studies of their hybrids with complementary DNA were carried out. All the four stereoisomers when present at 3'/5' terminal positions in the ODNs were almost equally efficient in their binding capacity as the natural oligomers, with (1S, 2S) being marginally favored over other stereoisomers. The incorporation of these chiral acyclic nucleosides also protected the ODN against enzymatic degradation.