Interactions of Cytosine Derivatives with T路A Interruptions in Pyrimidine路Purine路Pyrimidine DNA Triplexes

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Abstract
The ability of triplex-forming oligopyrimidines to interact with duplex targets which contain a single pyr路pur interruption in their homopurine triplex binding site was studied. These oligonucleotides contain either N4-(3-carboxypropyl)deoxycytidine (3) or N4-(5-carboxytriazolyl)deoxycytidine (4) to target the pyr路pur interruption. The 3-carboxypropyl and the 5-carboxytriazolyl groups of these cytosine derivatives are designed to span the major groove of the duplex target. Molecular models suggest that the carboxyl group of 3 or 4 can serve as a hydrogen bond acceptor for the N6-amino hydrogen of A in a T路A base pair. Additional contacts are possible between the N4-amino hydrogen of 3 or 4 and the O4-carbonyl oxygen of T. UV melting experiments showed that a 15-mer, I(3), containing nucleoside 3 formed a stable triplex with duplex targets containing a single T路A interruption. The melting temperature of this triplex was 7 掳C higher than that of a similar triplex containing a single G路T路A triad when a Tris buffer was employed. Oligomer I(3) also formed a triplex of lower stability with a target containing a G路C base pair but not with targets containing C路G, U路A, or A路T base pairs. A similar 15-mer, II, containing nucleoside 4 was found to be less selective than I(3) in its interaction with duplex targets. Thus, gel mobility shift experiments showed that in addition to interacting with T路A, oligomer II also formed triplexes with duplex targets containing U路A and C路G interruptions. These studies suggest that nucleoside derivatives which can potentially contact both bases of a pyr路pur interruption might provide a means to extend the range of sequences which can be recognized by triplex-forming oligonucleotides.