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

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 g roup in (1S, 2S), 4a, and (1R, 2R), 4d, was accomplished under Mitsunobu co nditions to get (IR, 2S), 4c, and (1S, 2R), 4e isomers, respectively Compou nds 4a-f were individually converted into their respective amidite synthons 5a-f. All these stereoisomers were individually incorporated into oligonuc leotides (ODNs) at pre-determined positions and various biophysical studies of their hybrids with complementary DNA were carried out. All the four ste reoisomers 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 incorporat ion of these chiral acyclic nucleosides also protected the ODN against enzy matic degradation. (C) 2001 Elsevier Science Ltd. All rights reserved.