期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 12, 页码 2484-2487出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.04.073
关键词
Nucleoside; Respiratory syncytial virus; Mitochondria; DNA polymerase gamma; Mitochondrial RNA polymerase
Novel 4'-substituted beta-D-2'-deoxy-2'-alpha-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of beta-D-2'-deoxy-2'-alpha-fluoro-4'-alpha-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. (C) 2015 Elsevier Ltd. All rights reserved.
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