Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase.

Autor: Wang G; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore., Lim SP; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore., Chen YL; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Hunziker J; Novartis Institutes for BioMedical Research, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland., Rao R; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore., Gu F; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Seh CC; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore., Ghafar NA; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore., Xu H; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore., Chan K; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Lin X; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Saunders OL; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Fenaux M; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Zhong W; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States., Shi PY; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Department of Biochemistry & Molecular Biology, Department of Pharmacology & Toxicology, Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States., Yokokawa F; Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States. Electronic address: fumiaki.yokokawa@novartis.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jul 15; Vol. 28 (13), pp. 2324-2327. Date of Electronic Publication: 2018 May 03.
DOI: 10.1016/j.bmcl.2018.04.069
Abstrakt: To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2'- and/or 4'-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2'-OH with 2'-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2'-fluorination, the introduction of fluorine at the ribose 4'-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2'-C-ethynyl-4'-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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