Synthesis of 2′-O-Methyl/2′-O-MOE-L-Nucleoside Derivatives and Their Applications: Preparation of G-Quadruplexes, Their Characterization, and Stability Studies

Nucleosides and their analogues constitute an important family of molecules with potential antiviral and antiproliferative activity. The enantiomers of natural nucleosides, l-nucleoside derivatives, which have comparable biological activity but more favorable toxicological properties and greater metabolic stability than d-nucleosides, have emerged as a new class of therapeutic agents. Furthermore, l-nucleosides can be used as a building block to prepare l-oligonucleotides, which have identical physical properties in terms of solubility, hybridization kinetics, and duplex thermal stability as d-oligonucleotides but completely orthogonal in nature. Consequently, they are resistant to nuclease degradation, nontoxic, and immunologically passive, which are desirable properties for biomedical applications. Herein, we describe the synthesis of several 2 '-O-methyl/2 '-O-MOE-l-nucleoside pyrimidine derivatives and their incorporation into G-rich oligonucleotides. Finally, we evaluated the stability and resistance against nucleases of these new G-quadruplexes, demonstrating the potential of the l-nucleosides described in this work in providing enhanced nuclease resistance with a minimal impact in the nucleic acid structural properties.

Automated summary

Nucleosides and their analogues, especially l-nucleosides, are important molecules with potential antiviral and antiproliferative activity. They have emerged as a new class of therapeutic agents due to their comparable biological activity, improved toxicological properties, and greater metabolic stability compared to d-nucleosides. l-nucleosides can also be used as building blocks for l-oligonucleotides, which have similar physical properties as d-oligonucleotides but are resistant to nuclease degradation, non-toxic, and immunologically passive. The synthesis and incorporation of 2'-O-methyl/2'-O-MOE-l-nucleoside pyrimidine derivatives into G-rich oligonucleotides were described, showing their potential in providing enhanced nuclease resistance without significant impact on nucleic acid structural properties.