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Aromatic vs . Carbohydrate Residues in the Major Groove: Synthesis of 5‐[(Benzyloxy)methyl]pyrimidine Nucleosides and Their Incorporation into Oligonucleotides
Author(s) -
Bertolini Reto,
Hunziker Jürg
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20000809)83:8<1962::aid-hlca1962>3.0.co;2-8
Subject(s) - chemistry , oligonucleotide , duplex (building) , pyrimidine , stereochemistry , ribose , nucleoside , uracil , dna , rna , biochemistry , gene , enzyme
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 H 2 O.