二磷酸核苷前体药物：DiPPro-化合物的合理开发

Title:Rational Development of Nucleoside Diphosphate Prodrugs: DiPPro-Compounds

Volume: 22 Issue: 34

Author(s): C. Meier, H. J. Jessen, T. Schulz, L. Weinschenk, F. Pertenbreiter and J. Balzarini

Affiliation:

关键词: 二磷酸核苷，先导核苷，先导药物，甲基异丙基环己烯酮，人类免疫缺陷病毒，DiPPro化合物，酶催化

摘要: The bio-reversible protection of nucleoside diphosphates is summarized. The design, hydrolytic characteristics, and the antiviral activity of these prodrugs of NDPs are described. In contrast to earlier attempts, the DiPPro-approach [β-(bis(acyloxybenzyl) nucleoside diphosphates)] leads to the successful delivery of the desired nucleoside diphosphates. The stability towards hydrolysis is dependent on the specific acyl moieties in the bis(acyloxybenzyl) unit as well as on the particular nucleoside analogue. Hydrolysis studies in aqueous PBS buffer (pH 7.3), 20 % human plasma in PBS, RPMI-1640 culture medium, and CEM cell extracts were carried out. Contrary to a high chemical and plasma stability, the compounds showed a very low half-life in CEM cell extracts, and efficiently released the nucleoside analogues diphosphates, e.g. of AZT, d4T and BVDU. Two additional types of cycloSal- NDP prodrugs were studied but neither proved to be useful as nucleoside diphosphate prodrugs. In summary, the results led to the development of a new series of non-symmetric nucleoside diphosphate prodrugs that selectively delivered the nucleoside diphosphate in cell extracts.

Cite this article as:

C. Meier, H. J. Jessen, T. Schulz, L. Weinschenk, F. Pertenbreiter and J. Balzarini , Rational Development of Nucleoside Diphosphate Prodrugs: DiPPro-Compounds, Current Medicinal Chemistry 2015; 22 (34) . https://dx.doi.org/10.2174/0929867322666150825163119