Chimie médicale

Synthesis and Biological Evaluation of Pyrrolidine Functionalized Nucleoside Analogs

Abstract

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.