Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides.
Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides.
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DOI：
10.1021/acs.jmedchem.5b00737
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发表时间：
2015-07
影响因子：
7.3
通讯作者：
L. Weinschenk;D. Schols;J. Balzarini;C. Meier
中科院分区：
文献类型：
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作者：
L. Weinschenk;D. Schols;J. Balzarini;C. Meier
非对称双磷酸核苷被描述为核苷二磷酸（NDP）递送系统。其原理是在NDP的β-磷酸段上附着不同的双（酰基氧苄基）基团。研究了含有两个烷酰苄基残基的DiPPro化合物和含有一个烷酰苄基或一个苯甲酰苄基作为生物可逆前药基团的DiPPro化合物。含有短链烷烃酯的化合物可以通过化学或酶的方法快速水解。第二前药组的酯基由长亲脂性脂肪族或芳香残基组成。该组的亲脂性使前药能够穿透细胞膜。引入两种不同的组可以控制逐步去除前药部分，从而在CEM细胞提取物中实现NDP的高选择性递送。这些化合物甚至在胸苷激酶缺陷的CEM细胞中也具有高度的抗HIV活性。因此，这些化合物虽然在α-磷酸基团上带电，但被细胞吸收并释放ndp。
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.