title: Ethyl 1,8-naphthyridone-3-carboxylates downregulate human papillomavirus-16 E6 and E7 oncogene expression.
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.
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino , 10043 Orbassano, Torino, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Donalisio
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Monica
authors.initials: M
authors.lastname: Argenziano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Valeria
authors.initials: V
authors.lastname: Cagno
authors.forename: Andrea
authors.initials: A
authors.lastname: Civra
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
authors.forename: Roberta
authors.initials: R
authors.lastname: Cavalli
authors.forename: David
authors.initials: D
authors.lastname: Lembo
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D027383:Papillomaviridae / Q000187:drug effects / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis*; D002583:Uterine Cervical Neoplasms / Q000235:genetics
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009287:Naphthyridines; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins