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PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer

Pertusati, Fabrizio, Hinsinger, Karen, Flynn, Áine Sinéad, Powell, Ned George, Tristram, Amanda Jane, Balzarini, Jan and McGuigan, Christopher 2014. PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer. European Journal of Medicinal Chemistry 78 , pp. 259-268. 10.1016/j.ejmech.2014.03.051

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: 5,6,7,8-Tetrahydro-1-naphthol; HIV; Antiproliferative activity; HPV; PMPA/PMEA
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 15 March 2014
Last Modified: 24 Nov 2020 15:53

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