期刊
CURRENT MEDICINAL CHEMISTRY
卷 22, 期 34, 页码 3933-3950出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929867322666150825163119
关键词
Nucleoside diphosphates; pronucleotides; prodrugs; cycloSal; HIV; DiPPro-compounds; enzymatic activation
资金
- University of Hamburg
- Deutsche Forschungsgemeinschaft (DFG) [Me1161/13-1]
- Geconcerteerde Onderzoeksacties (GOA) [019/05]
- Fonds voor Wetenschappelijk Onderzoek (FWO) - Vlaanderen
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 [beta-(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.
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