Recognition and cleavage of RNA and RNA analogs by zinc(II) macrocyclic complexes
Rossiter, Clifford S
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Once thought of only as a transient species involved in the conversion of DNA genetic information into proteins, RNA is now known to participate in various functions from catalysis to RNAi to serving as a genome in and of itself. The ability to manipulate these RNA cellular processes holds great promise in the development of novel therapeutics. One such way is to site selectively cleave RNA, thus disrupting its cellular functions. Studies done in the Morrow laboratory have focused on artificial metalloribonucleases that were capable of cleaving RNA under physiologically relevant conditions. Recent studies have shown a Zn(II) cyclen complex that resembles the cleaving agents studied in the Morrow laboratory are capable of recognizing the nucleobase of both thymidine and uridine. In this thesis, we demonstrate that RNA cleavage and nucleobase recognition utilize many of the same properties. Several Zn(II) macrocyclic complexes bind to uridine and that uridine (N3 - ) anion affinity of these Zn(II) complexes increases linearly with hydroxide affinity. Based on the above studies, a dinuclear Zn(II) macrocyclic complex was synthesized a studied for its ability to both recognize and cleave UpPNP, a RNA analog. These studies show that the dinuclear complex was capable of cleaving UpPNP faster then its mononuclear analog. A third project was started that utilized acridine as a recognition agent to specifically cleave RNA. Studies included in this thesis show the synthesis and solution characterization of the complex.