Title: 5-(1-Acetoxyvinyl)-cyclosaligenyl-2 ',3 '-dideoxy-2 ',3 '-didehydrothymidine monophosphates, a second type of new, enzymatically activated cyclosaligenyl pronucleotides
Authors: Gisch, Nicolas ×
Pertenbreiter, Florian
Balzarini, Jan
Meier, Chris #
Issue Date: Dec-2008
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:51 issue:24 pages:8115-8123
Abstract: In our attempt to further develop the cycloSal pronucleotide concept, we report oil 5-(1-acetoxyvinyl)-cycloSal-d4TMPs as a new type of enzyme-activated pronucleotides. These compounds were converted into 5-acetyl-cycloSal-d4TMPs by (carboxy)esterase cleavage inside the cells. The enzymatic reaction led to the formation of a strong electron-withdrawing substituent that strongly accelerates the chemical hydrolysis of the cycloSal nucleotide to give d4TMP. For some cycloSal-d4TMPs a separation into the diastereomers was achieved. The absolute configuration was assigned by correlation of circular dichroism spectra with similar compounds. Most of the compounds showed complete retention of antiviral activity in TK-deficient CEM/TK- cells, which proves the TK-bypass potential of this approach. Interestingly, (S-p)-isomers of cycloSal phosphate triesters showed better antiviral activity in HIV-2-infected thymidine-kinase deficient CEM/TK- cells than their (R-p)-counterparts.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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