gs-7340 and Papillomavirus-Infections

The synthesis and in vitro biological evaluation of novel phosphonamidate and phosphonodiamidate prodrugs of adefovir and tenofovir are reported. The selected synthetic approach from free phosphonic acid via bis-trimethylsilyl ester intermediates affords (L)-alanine ester derivatives in 10-70% yields. When assessed for their anti-HIV activity, all the prodrugs showed submicromolar activity. Noteworthy, the most potent derivative in the adefovir series contained a 5,6,7,8-tetrahydronaphtyl group, herein reported for the first time as an aryl moiety in a ProTide. A pronounced cytostatic activity of the above prodrugs is also reported. Selected compounds were tested for their antiproliferative activity against HPV-transformed cells and they were found significantly more active in comparison to their parent compounds. In this study a slightly improved activity of the adefovir derivatives over those of tenofovir was also noticed. However, no specificity for naturally HPV-transformed cell lines was observed.

Topics: Adenine; Antineoplastic Agents; Antiviral Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; HIV; HIV Infections; Humans; Microbial Sensitivity Tests; Molecular Structure; Organophosphonates; Papillomavirus Infections; Prodrugs; Structure-Activity Relationship; Tenofovir; Tumor Cells, Cultured