AI Article Synopsis
- Nucleoside and nucleotide analogues, particularly those with a sulfur atom replacing the ribose oxygen, show promise in treating viral infections and cancer.
- A new method combines biocatalytic nucleobase diversification and chemical functionalization to create a wide variety of nucleoside analogues from 4'-thiouridine.
- The approach successfully produced 5-iodo-4'-thiouridine enzymatically and led to a novel nucleoside analogue probe, 5-ethynyl-4'-thiouridine, which can monitor RNA synthesis in HeLa cells as a new tool for metabolic RNA labeling.
Article Abstract
Nucleoside and nucleotide analogues have proven to be transformative in the treatment of viral infections and cancer. One branch of structural modification to deliver new nucleoside analogue classes explores replacement of canonical ribose oxygen with a sulfur atom. Whilst biological activity of such analogues has been shown in some cases, widespread exploration of this compound class is hitherto hampered by the lack of a straightforward and universal nucleobase diversification strategy. Herein, we present a synergistic platform enabling both biocatalytic nucleobase diversification from 4'-thiouridine in a one-pot process, and chemical functionalization to access new entities. This methodology delivers entry across pyrimidine and purine 4'-thionucleosides, paving a way for wider synthetic and biological exploration. We exemplify our approach by enzymatic synthesis of 5-iodo-4'-thiouridine on multi-milligram scale and from here switch to complete chemical synthesis of a novel nucleoside analogue probe, 5-ethynyl-4'-thiouridine. Finally, we demonstrate the utility of this probe to monitor RNA synthesis in proliferating HeLa cells, validating its capability as a new metabolic RNA labelling tool.
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