Aromatic vs. Carbohydrate residues in the major groove: Synthesis of 5-[(benzyloxy)methyl]pyrimidine nucleosides and their incorporation into oligonucleotides

Article abstract of DOI:10.1002/1522-2675(20000809)83:8<1962::AID-HLCA1962>3.0.CO;2-8

The synthesis of 5-[(benzyloxy)methyl]-substituted pyrimidine 2'-deoxynucleosides 14 and 15 starting from the uracil derivative 6 and tetra-O-acetyl-D-ribose is described (Schemes 1-3). These nucleosides were converted to the corresponding cyanoethyl phosphoramidites 18 and 19, respectively, and incorporated into oligodeoxynucleotide decamers. The 5-[(benzyloxy)methyl]-nucleoside building blocks (bo)T(d) and (bom)C(d) (bo = benzyloxy, bom = (benzyloxy)methyl) - shape analogs of the naturally occurring glucosylated nucleosides 1 and 2 (see Fig. 1) - lead to weaker binding affinities of oligodeoxynucleotides pairing to DNA as well as RNA complements. The modification is more destabilizing in the case of (bo)T(d) than (bom)C(d). Analysis of the thermodynamics of duplex formation shows that (bo)T(d) and (bom)C(d) incorporation leads to a smaller entropy change in duplex formation that is, however, overcompensated by a less favorable enthalpy term. Molecular-modeling studies suggest that the benzyl groups reside in the major groove which would explain the improved pairing entropy as a result of the exclusion of ordered H₂O.