Affiliation:
1. Organic Chemistry Department of Chemistry Faculty of Mathematics, Informatics and Natural Sciences Universität Hamburg Martin‐Luther‐King‐Platz 6 D‐20146 Hamburg Germany
2. Laboratory of Virology and Chemotherapy Department of Microbiology and Immunology and Transplantation Rega Institute for Medical Research KU Leuven, Herestraat 49 Leuven B‐3000 Belgium
Abstract
AbstractNucleoside analogs require three phosphorylation steps catalyzed by cellular kinases to give their triphosphorylated metabolites. Herein, the synthesis of two types of triphosphate prodrugs of different nucleoside analogs is disclosed. Triphosphates comprising: i) a γ‐phosphate or γ‐phosphonate bearing a bioreversible acyloxybenzyl group and a long alkyl group and ii) γ‐dialkyl phosphate/phosphonate modified nucleoside triphosphate analogs. Almost selective conversion of the former TriPPPro‐compounds into the corresponding γ‐alkylated nucleoside triphosphate derivatives is demonstrated in CEM/0 cell extracts that proved to be stable toward further hydrolysis. The latter γ‐dialkylated triphosphate derivatives lead to the slow formation of the corresponding NDPs. Both types of TriPPPro‐compounds are highly potent in wild‐type CEM/0 cells and more importantly, they exhibit even better activities against HIV‐2 replication in CEM/TK− cell cultures. A finding of major importance is that, in primer extension assays, γ‐phosphate‐modified‐NTPs, γ‐mono‐alkylated‐triphosphates, and NDPs prove to be substrates for HIV‐RT but not for cellular DNA‐polymerases α,γ.
Funder
Deutsche Forschungsgemeinschaft
Society of the Friendly Sons of St. Patrick for the Relief of Emigrants from Ireland
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)
Cited by
1 articles.
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