title: Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex.
abstract: Selective recognition and alkylation of G-quadruplex oligonucleotides has been achieved by substituted naphathalene diimides (NDIs) conjugated to engineered phenol moieties by alkyl-amido spacers with tunable length and conformational mobility. FRET-melting assays, circular dichroism titrations and gel electrophoresis analysis have been carried out to evaluate both reversible stabilization and alkylation of the G-quadruplex. The NDIs conjugated to a quinone methide precursor (NDI-QMP) and a phenol moiety by the shortest alkyl-amido spacer exhibited a planar and fairly rigid geometry (modelled by DFT computation). They were the best irreversible and reversible G-quadruplex binders, respectively. The above NDI-QMP was able to alkylate the telomeric G-quadruplex DNA in the nanomolar range and resulted 100-1000 times more selective on G-quadruplex versus single- and double-stranded oligonucleotides. This compound was also the most cytotoxic against a lung carcinoma cell line.
authors.affiliation: Dipartimento di Istologia, Microbiologia e Biotecnologie Mediche, via Gabelli 63, Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Nadai
authors.forename: Filippo
authors.initials: F
authors.lastname: Doria
authors.forename: Marco
authors.initials: M
authors.lastname: Di Antonio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sattin
authors.forename: Luca
authors.initials: L
authors.lastname: Germani
authors.forename: Claudia
authors.initials: C
authors.lastname: Percivalle
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry* / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004354:Drug Screening Assays, Antitumor; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006801:Humans; D007094:Imides / Q000737:chemistry* / Q000378:metabolism; D045563:Indolequinones / Q000737:chemistry; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D007094:Imides; D045563:Indolequinones; D008024:Ligands; D009281:Naphthalenes; C068040:quinone methide; C542131:naphthalenediimide