Design of an N^7-Glycosylated Purine Nucleoside for Recognition of GC Base Pairs by Triple Helix Formation

Pyrimidine oligodeoxyribonucleotides bind in the major groove of DNA parallel to the purine Watson-Crick strand by formation of specific hydrogen bonds between thymine and adenine (T•AT triplet) and protonated cytosine and guanine (C+GC triplet) on the Hoogsteen face of the purine base. Alternatively, purine oligodeoxyribonucleotides bind in an antiparallel orientation relative to the purine Watson-Crick strand by formation of G•GC and A•AT triplets. The prerequisite protonation of cytosine in C+GC triplets leads to a considerable pH dependence in the binding affinity of C-containing oligodeoxyribonucleotides (Figure 1). Substitution of 5-methylcytosine (^mC) for cytosine results in increased binding affinities near physiological pH. In an attempt to eliminate the necessity for protonation, recent efforts have been directed toward the synthesis of nonnatural nucleosides which display the hydrogen bonding functionality of protonated cytosine.