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

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-04, Vol.20 (8), p.2581-2586
Main Authors: Robaldo, Laura, Izzo, Franco, Dellafiore, María, Proietti, Cecilia, Elizalde, Patricia V., Montserrat, Javier M., Iribarren, Adolfo M.
Format: Article
Language:English
Subjects:
2′-C-Methylnucleosides
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biocatalysis
Biological and medical sciences
Breast cancer
breast neoplasms
catalytic activity
Cell proliferation
Cell Proliferation - drug effects
Deoxyribozymes
DNA structures
DNA, Catalytic - antagonists & inhibitors
DNA, Catalytic - metabolism
DNA, Single-Stranded - antagonists & inhibitors
DNA, Single-Stranded - metabolism
DNAzymes
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Activation - drug effects
General pharmacology
Humans
Kinetics
Magnesium
Medical sciences
Miscellaneous
Modified nucleosides
Molecular Conformation
nucleosides
Pharmacology. Drug treatments
pyrimidines
Pyrimidines - chemistry
Pyrimidines - pharmacology
RNA
Stat3 protein
STAT3 Transcription Factor - antagonists & inhibitors
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
Structure-Activity Relationship
Tumor cell lines
Tumor Cells, Cultured
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Summary: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 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.02.047