Federico Faloci
| Expanding the Therapeutic Potential of Purine C-Nucleosides from Chemical Synthesis to Oligonucleotide Incorporation |
| Faloci Federico 1, Ghezzo Michele 1, Groaz Elisabetta 2,3, and Sissi Claudia 1 1 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy; 2 Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; 3 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium |
| Abstract Nucleoside and nucleotide analogues represent a diverse and versatile class of compounds in medicinal chemistry, that find applications for a range of therapeutic strategies as antiviral and anticancer treatments. Within this context, C-nucleosides are particularly attractive scaffolds, where the unstable C-N glycosidic bond is replaced by a more stable C–C bond. This feature imparts enhanced chemical and metabolic stability, as demonstrated by remdesivir, an FDA-approved broad-spectrum antiviral agent [1,2]. Additionally, this structural modification can alter base-pairing geometry, providing opportunities to modulate the physicochemical properties of nucleic acids [2,3]. Despite these advantages, the development of purine-based C-nucleosides and their incorporation into oligonucleotide architecture remains relatively underexplored. In this study, we explored the synthesis of 4-aza-7,9-dideazapurine C-nucleoside analogues, characterized by targeted modifications of the purine scaffold through N-C replacements within the heterocycle core, designed to modulate electronic distribution and intermolecular interactions. A convergent C-glycosylation approach, providing access to both adenine- and guanine-modified derivatives. In addition, selected adenosine derivatives were converted to the corresponding phosphoramidites and incorporated site-selectively into RNA sequences via automated solid-phase synthesis. This approach will provide novel purine C-nucleoside entities to be evaluate as both anticancer and antiviral therapeutic agents. Additionally, they will be used as functional building blocks to be inserted within oligonucleotide strands to assess their potential impact on the optimization of anticancer agents. |
| References [1] Radoshitzky, S.R.; Iversen, P.; et al. Expanded profiling of Remdesivir as a broad-spectrum antiviral and low potential for interaction with other medications in vitro. Sci Rep 2023, 13, 3131. https://doi.org/10.1038/s41598-023-29517-9 [2] Temburnikar, K.; Seley-Radtke, K. L. Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides. Beilstein J. Org. Chem. 2018, 14, 772–785. https://doi.org/10.3762/bjoc.14.65 [3] Vögele, J.; Duchardt-Ferner; et al. Structural and dynamic effects of pseudouridine modifications on noncanonical interactions in RNA. RNA 2023, 29, 790–807. https://doi.org/10.1261/rna.079506.122 |