Synthesis, Hybridization Characteristics,
and Fluorescence
Properties of Oligonucleotides Modified with Nucleobase-Functionalized
Locked Nucleic Acid Adenosine and Cytidine Monomers
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Abstract
Conformationally
restricted nucleotides such as locked nucleic
acid (LNA) are very popular as affinity-, specificity-, and stability-enhancing
modifications in oligonucleotide chemistry to produce probes for nucleic
acid targeting applications in molecular biology, biotechnology, and
medicinal chemistry. Considerable efforts have been devoted in recent
years to optimize the biophysical properties of LNA through additional
modification of the sugar skeleton. We recently introduced C5-functionalization
of LNA uridines as an alternative and synthetically more straightforward
approach to improve the biophysical properties of LNA. In the present
work, we set out to test the generality of this concept by studying
the characteristics of oligonucleotides modified with four different
C5-functionalized LNA cytidine and C8-functionalized LNA adenosine
monomers. The results strongly suggest that C5-functionalization of
LNA pyrimidines is indeed a viable approach for improving the binding
affinity, target specificity, and/or enzymatic stability of LNA-modified
ONs, whereas C8-functionalization of LNA adenosines is detrimental
to binding affinity and specificity. These insights will impact the
future design of conformationally restricted nucleotides for nucleic
acid targeting applications