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  • Title: Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides.
    Author: Weinschenk L, Schols D, Balzarini J, Meier C.
    Journal: J Med Chem; 2015 Aug 13; 58(15):6114-30. PubMed ID: 26125628.
    Abstract:
    Nonsymmetric DiPPro-nucleotides are described as nucleoside diphosphate (NDP) delivery systems. The concept is to attach different bis(acyloxybenzyl) moieties at the β-phosphate moiety of a NDP. DiPPro compounds bearing two alkanoylbenzyl residues and DiPPro compounds bearing an alkanoylbenzyl or a benzoylbenzyl group as bioreversible prodrug moieties were studied. Compounds bearing short chain alkanoyl esters led to a fast hydrolysis by chemical or enzymatic means. The ester group in the second prodrug group comprised a long lipophilic aliphatic or an aromatic residue. The lipophilicity of this group enabled the prodrug to penetrate the cell membrane. The introduction of two different groups allowed a controlled stepwise removal of the prodrug moieties to achieve a highly selective delivery of the NDP in CEM cell extracts. The compounds were highly active against HIV even in thymidine kinase-deficient CEM cells. Thus, the compounds, although charged at the α-phosphate group, were taken up by the cells and released NDPs.
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