Synthesis of peptidomimetic conjugates of cyclic nucleoside phosphonates

Abstract

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 nontoxic 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 with an alcoholic amino acid side chain (Ser, Tyr, and Thr) or 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 provides a procedure for synthesizing peptidomimetic conjugates of two broad-spectrum antiviral acyclic nucleoside phosphonates: (S)-HPMPC and (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.