Abstract
Modified nucleobase analogues can serve as powerful tools for changing physicochemical and biological properties of DNA or RNA. Guanosine derivatives containing bulky substituents at 8 position are known to adopt syn conformation of N-glycoside bond. On the contrary, in RNA the anti conformation is predominant in Watson-Crick base pairing. In this paper two 8-substituted guanosine derivatives, 8-methoxyguanosine and 8-benzyloxyguanosine, were synthesized and incorporated into oligoribonucleotides to investigate their influence on the thermodynamic stability of RNA duplexes. The methoxy and benzyloxy substituents are electron-donating groups, decreasing the rate of depurination in the monomers, as confirmed by N-glycoside bond stability assessments. Thermodynamic stability studies indicated that substitution of guanosine by 8-methoxy- or 8-benzyloxyguanosine significantly decreased the thermodynamic stability of RNA duplexes. Moreover, the presence of 8-substituted guanosine derivatives decreased mismatch discrimination. Circular dichroism spectra of modified RNA duplexes exhibited patterns typical for A-RNA geometry.
Highlights
Modified nucleic acids are a quickly growing class of compounds that have various uses
The results presented confirm that a methoxy or benzyloxy group introduced at the 8 position of a guanosine moiety significantly increases the stability of the N-glycoside bond
RNA duplexes containing 8-methoxy- or 8-benzyloxyguanosine are less stable compared with unmodified RNA due to the steric bulk of the substituents
Summary
Modified nucleic acids are a quickly growing class of compounds that have various uses. They can be successfully applied in investigations of nucleic acid structure and interactions between nucleic acids and proteins. Nucleoside analogs exhibit promising properties in vitro and in vivo as therapeutic agents, e.g., in gene silencing or in anti-viral and cancer therapy. In biological studies, they often serve as enzyme inhibitors and are able to inactivate the replication, transcription, translation, repair and processing pathways of nucleic acids [1,2,3]. The 8-substituted purine nucleosides exhibit promising anti-proliferative properties by inducing apoptosis of different cancer cell lines, e.g., multiple myeloma and other leukemias
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