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.
Anketell et al. (Thu,) studied this question.