Strong epidemiological and molecular data associate cervical cancer (CC) with high-risk human papillomavirus (HPV) infections. The carcinogenic mechanism depends mainly on the expression of E6 and E7 oncoproteins encoded by the viral genome. Using a cell-based high-throughput assay, an in-house library of compounds was screened identifying the 1,8-naphthyridone 1 that efficiently inhibited the transcription driven by the long control region of the HPV genome. A series of analogues were then synthesized, obtaining more potent derivatives able to downregulate E6 and E7 transcripts in HPV-16-positive CC CaSki cells. An unusual structural insight emerged for the C-3 position of the 1,8-naphthyridone core, where the ethyl carboxylate esters, but not the carboxylic acids, are responsible for the activity. In vitro uptake studies showed that the 3-ethyl carboxylates do not act as prodrugs. The 1,8-naphthyridones emerged as valid starting points for the development of innovative agents potentially useful for the treatment of HPV-induced CC.

Ethyl 1,8-Naphthyridone-3-carboxylates Downregulate Human Papillomavirus-16 (HPV-16) E6 and E7 Oncogenes Expression

DONALISIO, Manuela;ARGENZIANO, MONICA;CAGNO, VALERIA;CIVRA, ANDREA;CAVALLI, Roberta;LEMBO, David;
2014-01-01

Abstract

Strong epidemiological and molecular data associate cervical cancer (CC) with high-risk human papillomavirus (HPV) infections. The carcinogenic mechanism depends mainly on the expression of E6 and E7 oncoproteins encoded by the viral genome. Using a cell-based high-throughput assay, an in-house library of compounds was screened identifying the 1,8-naphthyridone 1 that efficiently inhibited the transcription driven by the long control region of the HPV genome. A series of analogues were then synthesized, obtaining more potent derivatives able to downregulate E6 and E7 transcripts in HPV-16-positive CC CaSki cells. An unusual structural insight emerged for the C-3 position of the 1,8-naphthyridone core, where the ethyl carboxylate esters, but not the carboxylic acids, are responsible for the activity. In vitro uptake studies showed that the 3-ethyl carboxylates do not act as prodrugs. The 1,8-naphthyridones emerged as valid starting points for the development of innovative agents potentially useful for the treatment of HPV-induced CC.
2014
57
13
5649
5663
HPV; cervical cancer.; quinolones
Manuela Donalisio;Serena Massari;Monica Argenziano;Giuseppe Manfroni;Valeria Cagno;Andrea Civra;Stefano Sabatini;Violetta Cecchetti;Arianna Loregian;Roberta Cavalli;David Lembo;Oriana Tabarrini
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/148705
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