Influence of conformationally restricted pyrimidines on the activity of 10-23 DNAzymes

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• 作者：Laura Robaldo^a ; Franco Izzo^b ; Marí ; a Dellafiore^a ; Cecilia Proietti^b ; Patricia V. Elizalde^b ; Javier M. Montserrat^a ; ^c ; Adolfo M. Iribarren^a ; ^d ; ^{airibarren@unq.edu.ar}
• 关键词：Deoxyribozymes ; DNAzymes ; DNA structures ; 2&prime ; -C-Methylnucleosides ; Modified nucleosides
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 April, 2012
• 年：2012
• 卷：20
• 期：8
• 页码：2581-2586
• 全文大小：534 K

文摘

The catalytic core of a 10-23 DNAzyme was modified introducing conformationally restricted nucleosides such as (2?em>R)-, (2?em>S)-2?deoxy-2?C-methyluridine, (2?em>R)-, (2?em>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 Mg²⁺ concentrations using a short RNA substrate. At low Mg²⁺ 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.