title: Design, synthesis, biophysical and biological studies of trisubstituted naphthalimides as G-quadruplex ligands.
abstract: A series of trisubstituted naphthalimides have been synthesized and evaluated as telomeric G-quadruplex ligands by biophysical methods. Affinity for telomeric G-quadruplex AGGG(TTAGGG)(3) binding was first screened by fluorescence titrations. Subsequently, the interaction of the telomeric G-quadruplex with compounds showing the best affinity has been studied by isothermal titration calorimetry and UV-melting experiments. The two best compounds of the series tightly bind the telomeric quadruplex with a 2:1 drug/DNA stoichiometry. These derivatives have been further evaluated for their ability to inhibit telomerase by a TRAP assay and their pharmacological properties by treating melanoma (M14) and human lung cancer (A549) cell lines with increasing drug concentrations. A dose-dependent inhibition of cell proliferation was observed for all cellular lines during short-term treatment.
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, Via Ponte don Melillo, 84084 Fisciano (SA), Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.forename: Bruno
authors.initials: B
authors.lastname: Pagano
authors.forename: Carmen
authors.initials: C
authors.lastname: Petronzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Massa
authors.forename: Veronica
authors.initials: V
authors.lastname: Esposito
authors.forename: Antonella
authors.initials: A
authors.lastname: Virgilio
authors.forename: Francesco
authors.initials: F
authors.lastname: Paduano
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Filomena
authors.initials: F
authors.lastname: Fiorito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Florio
authors.forename: Concetta
authors.initials: C
authors.lastname: Giancola
authors.forename: Aldo
authors.initials: A
authors.lastname: Galeone
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
mesh_terms: D000818:Animals; D002151:Calorimetry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D053644:Naphthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D053644:Naphthalimides; D019098:Telomerase