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

doi:10.1007/s00044-021-02700-1

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

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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 S_NAr 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 language	English (US)
Pages (from-to)	483-499
Number of pages	17
Journal	Medicinal Chemistry Research
Volume	30
Issue number	2
DOIs	https://doi.org/10.1007/s00044-021-02700-1
State	Published - Feb 2021

Bibliographical note

Funding Information:
We acknowledge Prof. Robert Vince (University of Minnesota) for his suggestion to conduct antiviral studies with pyrrolidine-substituted nucleosides and for his help with anti-HIV testing. We thank Profs. David Ferguson and Daniel Harki (University of Minnesota) for conducting the anticancer activity testing and Dr. Vijay Kumar (University of Minnesota) for his helpful edits on the final version of the manuscript. This work was supported in part by the Engebretson Grant for Drug Development from the University of Minnesota College of Pharmacy and a Grant-in-Aid grant from the University of Minnesota Graduate School.

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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This output contributes to the following UN Sustainable Development Goals (SDGs)

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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.]",

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AU - Geraghty, Robert J.

AU - Dreis, Christine

AU - Pujari, Suresh S.

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N2 - 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.]

AB - 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.]

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Synthesis and biological evaluation of pyrrolidine-functionalized nucleoside analogs

Abstract

Bibliographical note

Keywords

UN SDGs

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