A unified platform for nucleoside analog synthesis.
basic_science · Level V
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- Record sourced from PubMed, PMID 41785328.
- Also identified by DOI 10.1126/science.aed6880.
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Abstract
Nucleoside analogs (NAs) are essential as antiviral and anticancer therapies. Despite decades of focused medicinal chemistry efforts, their related chemical space remains underexplored, mainly due to their lengthy, single-molecule-oriented syntheses that lack the flexibility required to generate NA libraries. Here we report a flexible, robust, and efficient platform for the high-throughput synthesis of NAs using a photoredox coupling strategy. This approach produces both C- and N-linked NAs, and unifies the synthesis of several disparate NA classes, including 4'-thio, 4'-imino, and ProTides, all from a simple, scalable intermediate. Using this platform, we demonstrate the production of a diverse NA library and identify several hit compounds with anti-HIV-1 activity. We expect this new approach to NAs will inspire and support drug discovery efforts in this area.