Rational development of nucleoside diphosphate prodrugs: DiPPro-compounds

The bio-reversible protection of nucleoside diphosphates is summarized. The design, the hydrolysis behavior, and the antiviral activity of these prodrugs of NDPs are described. In contrast to earlier attempts, the DiPPro-approach [-(bis (acyloxybenzyl) nucleoside diphosphates)] successfully led to the delivery of the nucleoside diphosphates. It was proven [by hydrolysis studies in aqueous PBS buffer (pH 7.3), 20 % human plasma in PBS, RPMI-1640 culture medium, and CEM cell extracts] that the stability towards hydrolysis was dependent on the acyl moieties in the bis (acyloxybenzyl) unit as well as on the nucleoside analogue. 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 types of cycloSal-NDP prodrugs were also initially studied but proved to be not useful as nucleoside diphosphate prodrugs. Finally the obtained results led to the development of non-symmetric nucleoside diphosphate prodrugs that selectively deliver the nucleoside diphosphate in cell extracts.status: publishe