Uthpala Seneviratne, Susith Wickramaratne, Delshanee Kotandeniya, Arnold S. Groehler, Robert J. Geraghty, Christine Dreis, Suresh S. Pujari, and Natalia Y. Tretyakova*
Inhibition of viral reverse transcriptases and mammalian DNA polymerases by unnatural nucleoside analogues is a proven approach in antiviral and anticancer therapy, respectively. The majority of current nucleoside drugs retain the canonical nucleobase structure, which is fused to an unnatural sugar. In the present work, a series of novel pyrrolidine-functionalized purine and pyrimidine nucleosides was prepared via PyBOP-catalyzed SNAr addition-elimination reactions of commercial halogenated precursors and tested for their antiviral and anticancer activity. The newly synthesized nucleoside analogues showed limited biological activity, probably as a result of their poor cellular uptake and their inefficient bioactivation to the corresponding nucleoside monophosphates. A phosphoramidate prodrug, had improved cell permeability and was metabolized to the nucleoside monophosphate form in human cells, as revealed by HPLC-MS/MS analyses.
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