Synthesis of peptidomimetic conjugates of cyclic nucleoside phosphonates.
Synthesis of peptidomimetic conjugates of cyclic nucleoside phosphonates.
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DOI：
10.1002/0471142700.nc1504s43
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发表时间：
2010-12
影响因子：
--
通讯作者：
McKenna, Charles E
中科院分区：
文献类型：
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作者：
Serpi, Michaela;Krylov, Ivan S;Zakharova, Valeria M;McKenna, Charles E
Cyclic nucleoside phosphonates connected through a P-O-C linkage to a promoiety represent a class of prodrugs designed to overcome the low oral bioavailability of parent antiviral acyclic nucleoside phosphonates. In our prodrug approach, a non-toxic promoiety such as an amino acid or dipeptide is conjugated to the cyclic form of the parent drug by esterification of the phosphonic acid moiety by an alcoholic amino acid side chain (Ser, Tyr, and analogues) or through a glycol linker. For the biological evaluation and investigation of the pharmacokinetic profiles of these modified nucleoside phosphonates, a reliable synthetic procedure that allows preparation of sufficient amount of potential prodrugs is needed. This unit describes a method for generating peptidomimetic conjugates of two potent antiviral acyclic nucleoside phosphonates: 1-[(2S)-3-hydroxy-2-phosphonomethoxypropyl]cytosine ((S)-HPMPC, and 9-[(2S)-3-hydroxy-2-phosphonomethoxypropyl]adenine ((S)-HPMPA). Two alternate strategies allowing synthesizing selected amino acid, dipeptide, or ethylene glycol-linked amino acid prodrugs of (S)-HPMPC and (S)-HPMPA in solution and using a solid-phase approach are presented.
