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

Pertusati, Fabrizio ORCID:, Hinsinger, Karen, Flynn, Áine Sinéad, Powell, Ned George, Tristram, Amanda Jane, Balzarini, Jan and McGuigan, Christopher ORCID: 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: 17 Feb 2024 17:20

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