Influence of conformationally restricted pyrimidines on the activity of 10-23 DNAzymes.
2012
Abstract The catalytic core of a 10–23 DNAzyme was modified introducing conformationally restricted nucleosides such as (2′ R )-, (2′ S )-2′-deoxy-2′- C -methyluridine, (2′ R )-, (2′ S )-2′-deoxy-2′- C -methylcytidine, 2,2′-anhydrouridine and LNA-C, in one, two or three positions. Catalytic activities under pseudo first order conditions were compared at different Mg 2+ concentrations using a short RNA substrate. At low Mg 2+ concentrations, triple modified DNAzymes with similar kinetic performance to that displayed by the non-modified control were identified. In the search for a partial explanation of the obtained results, in silico studies were carried out in order to explore the conformational behavior of 2′-deoxy-2′- C -methylpyrimidines in the context of a loop structure, suggesting that at least partial flexibility is needed for the maintenance of activity. Finally, the modified 2′- C -methyl DNAzyme activity was tested assessing the inhibition of Stat3 expression and the decrease in cell proliferation using the human breast cancer cell line T47D.
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