PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer
- Eur J Med Chem. 2014 May 6:78:259-68. doi: 10.1016/j.ejmech.2014.03.051.
- 1. School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK.
- 2. HPV Oncology Research Group, Institute of Cancer and Genetics, School of Medicine, Cardiff University, UK.
- 3. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
- 4. School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: [email protected].
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.