Synthesis And Anti-Hiv Activity Of Cyclic Pyrimidine Phosphonomethoxy Nucleosides And Their Prodrugs: A Comparison Of Phosphonates And Corresponding Nucleosides

Abstract

Cyclic phosphonomethoxy pyrimidine nucleosides that are bioisosteres of the monophosphate metabolites of HIV reverse transcriptase (RT) inhibitors AZT, d4T, and ddC have been synthesized. The RT inhibitory activities of the phosphonates were reduced for both dideoxy (dd) and dideoxydidehydro (d4) analogs compared to the nucleosides. Bis-isopropyloxymethylcarbonyl (BisPOC) prodrugs were prepared on selected compounds and provided > 150-fold improvements in antiviral activity.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…The same procedure was reported by Mackman et al 31 to prepare bis(POC)-5′-phosphonomethoxy prodrugs of potent nucleosides such as d4T, AZT, ddC, or ddT. Phosphonomethoxy-d4T and -ddC derivatives were synthesized by electrophilic addition of dimethyl hydroxymethyl phosphonate to furanoid glycal 41 .…”

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

“…The antiviral potency of CNPs can also be improved considerably by the application of bis-(POC) prodrug technology. As a representative example, bis-(POC)-d4TP (22) has been reported to improve 29-fold the HIV antiretroviral activity of the corresponding nucleoside ( Figure 8) [23].…”

“…In an effort to identify new nucleoside inhibitors of reverse trascriptase, phosphonomethoxy analogues of cyclic pyrimidine nucleotide were synthesized and compared for their antiviral activity [23]. Among them, only d4TP (16; Figure 3) showed an antiviral activity below 200 mM.…”

Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals

“…The parent nucleoside proved to be completely inactive against HIV replication in cell cultures. In contrast, the triphosphate form of d4U is one of the most effective inhibitors of the HIV's RT 31 .…”