title: Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors.
abstract: A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Epigenetic Med Chem Lab, Università degli Studi di Salerno, Via Ponte Don Melillo, I-84084 Fisciano (SA), Italy. gsbardella@unisa.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Sara
authors.initials: S
authors.lastname: Bartolini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Ciro
authors.initials: C
authors.lastname: Milite
authors.forename: Marisabella
authors.initials: M
authors.lastname: Santoriello
authors.forename: Serena
authors.initials: S
authors.lastname: Orlando
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sciamanna
authors.forename: Annalucia
authors.initials: A
authors.lastname: Serafino
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.forename: Corrado
authors.initials: C
authors.lastname: Spadafora
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D015394:Molecular Structure; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C568465:2-(sec-butylthio)-6-(1-(2,6-difluorophenyl)propyl)-5-methylpyrimidin-4(3H)-one; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors