Protecting-Group-Mediated Diastereoselective Synthesis of C4′-Methylated Uridine Analogs and Their Activity against the Human Respiratory Syncytial Virus

Abstract

Adjusting the protecting group strategy, from an alkyl ether to a bidentate ketal at the carbohydrate backbone of uridine, facilitates a switchable diastereoselective α- or β-C4′/C5′-spirocyclopropanation. Using these spirocyclopropanated nucleosides as key intermediates, we synthesized a variety of C4′-methylated d-ribose and l-lyxose-configured uridine derivatives by a base-mediated ring-opening of the spirocyclopropanol moiety. Investigations of antiviral activity against the human respiratory syncytial virus were carried out for selected derivatives, showing moderate activity.

In silico design of a novel nucleotide antiviral agent by free energy perturbation

“…4'-C-methyl-uridine nucleoside derivatives have been widely studied against HIV, HBV and Yellow fever previously, but none of them were active up to 10 µM (Griffon et al, 2003). However, 4'-C-methyl-uridine nucleoside showed activity against human respiratory syncytial virus Relative to a model of UMP in the UMPK active site (prepared model from PDB ID -2UKD) (Köllmann et al, 2020). Moreover, 4'-modified nucleosides were reported to be active against flaviviruses, pestiviruses and HCV (Gosselin et al, 2003a;2003b).…”

Diversification of 4′-Methylated Nucleosides by Nucleoside Phosphorylases

“…As such, modified nucleosides mimicking their natural counterparts have a long history in medicinal and biological chemistry. − Today, modified nucleosides are indispensable pharmaceuticals for the treatment of various types of cancer and viral infections and further represent important tools in chemical biology for a spectrum of imaging applications. , Despite the great demand for these molecules, the synthesis of nucleosides is still regarded as challenging and inefficient . While nucleosides with ribosyl or 2′-deoxyribosyl moieties can be accessed from naturally occurring nucleosides or carbohydrates, − the preparation of sugar-modified nucleosides typically suffers from lengthy reaction sequences and low total yields. − Furthermore, a heavy reliance on protecting groups entails low overall efficiencies, and several sugar modifications at the 2′ or 4′ positions are known to limit diastereoselectivity in glycosylation approaches, , severely complicating the synthetic access to many target compounds. More importantly, established routes typically exhibit a lack of divergence as they tend to be specific to one nucleoside.…”

Stereodivergent Synthesis of Biologically Active Spironucleoside Scaffolds via Catalytic Cyclopropanation of 4-exo-Methylene Furanosides

“…In particular, nucleoside analogues have met a large success by their direct use as antiviral and anticancer agents and as enhancers of ssRNA and ssDNA binding properties . Recently, spirocyclic nucleoside derivatives have generated interest for their various biological properties . More precisely, 4-spirocyclic furanoses are interesting scaffolds that can restrict the side chain mobility of natural nucleosides. , In the course of studies toward novel nucleoside therapeutics, we were particularly attracted to furanose building blocks bearing a 4-spirocyclopropyl ester moiety, as a suitable and useful synthetic handle.…”