A guide for the synthesis of key nucleoside scaffolds in drug discovery

Rajapaksha, Dinithi G.; Mondal, Subhojit; Wang, Jason W.; Meanwell, Michael W.

doi:10.1007/s00044-023-03096-w

“…Many reviews dealing with nucleoside antivirals were published. Recent examples are accounts on fluorinated nucleosides [ 10 , 11 ], 4′-modified nucleosides [ 12 ], oxetanocin [ 13 , 14 ], marketed nucleosides [ 15 ], antiviral nucleosides and analogues [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], and the chemistry of nucleoside drugs [ 36 , 37 , 38 ]. However, these reviews predominantly consider chemical and structural aspects, with some discussion on the main nucleoside mechanisms of antiviral action [ 21 , 22 , 24 , 29 , 30 , 34 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

Kamzeeva,

Aralov,

Alferova

et al. 2023

CIMB

View full text Add to dashboard Cite

The search for new drugs has been greatly accelerated by the emergence of new viruses and drug-resistant strains of known pathogens. Nucleoside analogues (NAs) are a prospective class of antivirals due to known safety profiles, which are important for rapid repurposing in the fight against emerging pathogens. Recent improvements in research methods have revealed new unexpected details in the mechanisms of action of NAs that can pave the way for new approaches for the further development of effective drugs. This review accounts advanced techniques in viral polymerase targeting, new viral and host enzyme targeting approaches, and prodrug-based strategies for the development of antiviral NAs.

show abstract

Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Wang,

Shen,

Yan

et al. 2024

Angewandte Chemie

0

View full text Add to dashboard Cite

Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2′‐position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2′‐a‐aryl/alkenyl nucleosides via an electrochemical nickel‐catalyzed cross‐coupling of 2'‐bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2′‐ a‐aryl/ alkenyl nucleosides with excellent stereoselectivities, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2′‐aryl‐modified thymidine moieties and demonstrated that their annealed double‐stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2′‐aryl modifications at the 3′ end showed enhanced resistance to 3′‐exonuclease degradation and C2′‐aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.

show abstract

Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Wang,

Shen,

Yan

et al. 2024

Angew Chem Int Ed

0

View full text Add to dashboard Cite

Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2′‐position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2′‐a‐aryl/alkenyl nucleosides via an electrochemical nickel‐catalyzed cross‐coupling of 2'‐bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2′‐ a‐aryl/ alkenyl nucleosides with excellent stereoselectivities, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2′‐aryl‐modified thymidine moieties and demonstrated that their annealed double‐stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2′‐aryl modifications at the 3′ end showed enhanced resistance to 3′‐exonuclease degradation and C2′‐aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.

show abstract

A guide for the synthesis of key nucleoside scaffolds in drug discovery

Cited by 8 publications

References 81 publications

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Contact Info

Product

Resources

About