GENERALIZED TRIPLEX FORMATION USING NUCLEOSIDE ANALOGS

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DNA triple helix formation will be examined in a systematic manner for by exploiting various base analogues in order to study a series of base triplet recognition motifs. For example, we will examine eight different recognition motifs for the targeting of homopurine sequences. These eight motifs include two motifs each of (i) the antiparallel-stranded purine- purine-pyrimidine motif (e.g., see graphic below), (ii) the antiparallel- stranded pyrimidine-purine-pyrimidine motif, (iii) the antiparallel- stranded mixed base motif, and (iv) the parallel-stranded pyrimidine- purine-pyrimidine motif. Various nucleoside analogues will be prepared as needed in order to characterize and study each type of recognition motif. The targeting of pyrimidine-purine base pairs using both antiparallel- stranded and parallel-stranded base triplets will also be undertaken. The purine-pyrimidine-purine triplet motif GTA will be further developed by examining various N2-aminopurine analogues, as well as those containing appended functionality, for their ability to enhance hydrogen bonding/base stacking interactions. Xanthosine (Xn) will be studied for its ability to form the related purine-pyrimidine-purine triplet XnCG. Other pyrimidines or smaller surrogate heterocycles will be functionalized to provide hydrogen bonding characteristics and then examined for their ability to mediate triplex formation. The systematic nature of this study, as well as the advantages of using specifically designed base analogues, should provide important insights into the formation and stability of a variety of triple helix complexes, and provide a route to the generalized targeting of double-stranded sequences of DNA.