Synthesis and biological evaluation of pyrrolidine-functionalized nucleoside analogs

Uthpala Seneviratne, Susith Wickramaratne, Delshanee Kotandeniya, Arnold S. Groehler, Robert J. Geraghty, Christine Dreis, Suresh S. Pujari, Natalia Y. Tretyakova

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Inhibition of viral reverse transcriptases and mammalian DNA polymerases by unnatural nucleoside analogs 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 analogs 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 an improved cell permeability and was metabolized to the nucleoside monophosphate form in human cells, as revealed by HPLC-MS/MS analyses. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)483-499
Number of pages17
JournalMedicinal Chemistry Research
Volume30
Issue number2
DOIs
StatePublished - Feb 1 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Keywords

  • HIV
  • Nucleoside
  • Phosphoramidate
  • Prodrug
  • Reverse transcriptase
  • Synthesis

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