TY - JOUR
T1 - Synthesis and biological evaluation of pyrrolidine-functionalized nucleoside analogs
AU - Seneviratne, Uthpala
AU - Wickramaratne, Susith
AU - Kotandeniya, Delshanee
AU - Groehler, Arnold S.
AU - Geraghty, Robert J.
AU - Dreis, Christine
AU - Pujari, Suresh S.
AU - Tretyakova, Natalia Y.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
PY - 2021/2/1
Y1 - 2021/2/1
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.]
KW - HIV
KW - Nucleoside
KW - Phosphoramidate
KW - Prodrug
KW - Reverse transcriptase
KW - Synthesis
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U2 - 10.1007/s00044-021-02700-1
DO - 10.1007/s00044-021-02700-1
M3 - Article
AN - SCOPUS:85100490135
SN - 1054-2523
VL - 30
SP - 483
EP - 499
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 2
ER -
