Synthesis and biological evaluation of pyrrolidine-functionalized nucleoside analogs

被引：0
作者：
Uthpala Seneviratne
Susith Wickramaratne
Delshanee Kotandeniya
Arnold S. Groehler
Robert J. Geraghty
Christine Dreis
Suresh S. Pujari
Natalia Y. Tretyakova
机构：
[1] University of Minnesota,Department of Chemistry
[2] University of Minnesota,Masonic Cancer Center
[3] University of Minnesota,Department of Medicinal Chemistry
[4] University of Minnesota,Center for Drug Design
来源：
Medicinal Chemistry Research | 2021年 / 30卷
关键词：
HIV; Nucleoside; Reverse transcriptase; Phosphoramidate; Prodrug; Synthesis;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
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页码：483 / 499
页数：16
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