title: Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.
abstract: Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.
authors: Dipartimento di Scienze Farmaceutiche, Alma Mater Studiorum, University di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors: Andrea
authors: A
authors: Milelli
authors: Vincenzo
authors: V
authors: Tumiatti
authors: Marialuisa
authors: M
authors: Micco
authors: Michela
authors: M
authors: Rosini
authors: Guendalina
authors: G
authors: Zuccari
authors: Lizzia
authors: L
authors: Raffaghello
authors: Giovanna
authors: G
authors: Bianchi
authors: Vito
authors: V
authors: Pistoia
authors: J
authors: J
authors: Fernando Díaz
authors: Benet
authors: B
authors: Pera
authors: Chiara
authors: C
authors: Trigili
authors: Isabel
authors: I
authors: Barasoain
authors: Caterina
authors: C
authors: Musetti
authors: Marianna
authors: M
authors: Toniolo
authors: Claudia
authors: C
authors: Sissi
authors: Stefano
authors: S
authors: Alcaro
authors: Federica
authors: F
authors: Moraca
authors: Maddalena
authors: M
authors: Zini
authors: Claudio
authors: C
authors: Stefanelli
authors: Anna
authors: A
authors: Minarini
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D054856:G-Quadruplexes / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007094:Imides / Q000138:chemical synthesis* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D019914:Taq Polymerase / Q000037:antagonists & inhibitors / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics; D013816:Thermodynamics
chemical_list: C429685:1,4,5,8-naphthalenetetracarboxylic diimide; D000970:Antineoplastic Agents; D003603:Cytotoxins; D007094:Imides; D009281:Naphthalenes; D048049:Extracellular Signal-Regulated MAP Kinases; D019914:Taq Polymerase; D019098:Telomerase; D020169:Caspases