Convertible and Constrained Nucleotides: The 2’-Deoxyribose 5’-C-Functionalization Approach, a French Touch

Abstract

Many strategies have been developed to modulate the biological or biotechnical properties of oligonucleotides by introducing new chemical functionalities or by enhancing their affinity and specificity while restricting their conformational space. Among them, we review our approach consisting of modifications of the 5’-C-position of the nucleoside sugar. This allows the introduction of an additional chemical handle at any position on the nucleotide chain without disturbing the Watson–Crick base-pairing. We show that 5’-C bromo or propargyl convertible nucleotides (CvN) are accessible in pure diastereoisomeric form, either for nucleophilic displacement or for CuAAC conjugation. Alternatively, the 5’-carbon can be connected in a stereo-controlled manner to the phosphate moiety of the nucleotide chain to generate conformationally constrained nucleotides (CNA). These allow the precise control of the sugar/phosphate backbone torsional angles. The consequent modulation of the nucleic acid shape induces outstanding stabilization properties of duplex or hairpin structures in accordance with the preorganization concept. Some biological applications of these distorted oligonucleotides are also described. Effectively, the convertible and the constrained approaches have been merged to create constrained and convertible nucleotides (C2NA) providing unique tools to functionalize and stabilize nucleic acids.

Chemical Biology of G-quadruplex and i-motif DNA: use of topologically constrained DNA

“…The design of constrained DNA in the chemical biology research domain has already been investigated. As an example, Escudier et al have developed modified oligonucleotides in which the phosphodiester internucleotidic linkage is replaced with a dioxo-1,3,2-oxaza-phosphorinane moiety resulting in conformationally constrained nucleotides (CNA) [23]. In the case of G-quadruplex, the use of various templates to pre-organize G-quartet assemblies has also been described by different groups [24][25][26][27].…”

Functionalized oligonucleotides, synthetic catalysts as enzyme mimics

“…As the chemical strategies to introduce modifications have been reviewed in the literature by numerous groups [21,22] and ourselves [23], we will only present the functionalized monomers of interest in charge of the catalytic activities.…”