Twelve mono and dinucleating dipicolylamine(dpa)-based ligands have been designed and synthesized to investigate the catalytic activity of their corresponding zinc complexes toward the hydrolysis of phosphodiester bonds of RNA model substrates. The identity and stoichiometry of the metal complexes in solution were evaluated by potentiometric pH titrations, in water and/or in the binary solvent mixture DMSO:H<sub>2</sub>O (67%:33%), for four potentially dinucleating dpa-based ligands: <i>N,N,N’,N’-</i>tetrakis[(2-pyridyl)methyl]-2,6-diamino-<i>p</i>-nitrophenol (LOH), <i>N,N,N’,N’-</i>tetrakis[(6-amino-2-pyridyl)methyl]-2-hydroxy-1,3-diaminopropane (LOH’), 1,3-Bis[bis(pyridine-2-ylmethyl)amino]-propan-2-ol (L<sup>1</sup>OH) and <i>N,N,N’,N’</i>-tetrakis[(6-amino-2-pyridyl)methyl]-2,6-diamino-<i>p</i>-nitrophenol (L<sup>1</sup>OH’). Results showed that all ligands in the presence of Zn(II) are able to form mononuclear and dinuclear complexes but their stability is strongly affected by the presence of the amino groups in the dipicolylamine core and dependent on the nature of the bridging unit (phenol or alcohol group). In general, the ligand L<sup>1</sup>OH’ forms the less stable zinc complexes and mainly mononuclear species, whereas LOH’ forms the most stable dinuclear complexes. The introduction of hydrogen bonding functionalities also affects the basicity of the ligands, which is enhanced, and decreases the p<i>K</i><sub>a</sub> of a zinc-bound water molecule by ca. two p<i>K</i><sub>a</sub> units. The catalytic efficiency of metal complexes of the ligands with four amino hydrogen bonding groups (L<sup>1</sup>OH’ and LOH’) has been tested on small RNA models and the mechanism of catalysis was investigated with the help of inhibition, Solvent Kinetic Isotope Effect (SKIE) and computational studies. The cleavage rate of HPNPP, an activated RNA model, as well as the more stable substrate UpU, is accelerated of a million fold over the uncatalyzed reaction in water, at 25°C and neutral pH. Geometry optimisations and SKIE suggest a general base catalysis with proton transfer. The catalytic ability of dinickel(II), dicobalt(II), dicopper(II) and dicadmium(II) complexes of the ligand LOH’ was also investigated and found to follow the order: Ni(II) >> Co(II) > Cd(II) >> Cu(II). The X-Ray crystal structure of the complex [Zn<sub>2</sub>(LOH’)] with 4-nitrophenol phosphate reveals that the phosphodiester dianion binds the complex by bridging the two Zn(II) atoms and hydrogen bonding the four amino groups. These interactions are responsible for the enhanced reactivity of the most active dinuclear zinc catalyst for phosphodiesters hydrolysis reported to date.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:659890 |
| Date | January 2008 |
| Creators | Natale, Daniela |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/15494 |
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