title: Molecular modelling studies, synthesis and biological activity of a series of novel bisnaphthalimides and their development as new DNA topoisomerase II inhibitors.
abstract: A series of bisnaphthalimide derivatives were synthesized and evaluated for growth-inhibitory property against HT-29 human colon carcinoma. The N,N'-bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]propane-2-ethanediamine (9) and the N,N'-Bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]butylaminoethyl]-2-propanediamine (12) derivatives emerged as the most potent compounds of this series. Molecular modelling studies indicated that the high potency of 12, the most cytotoxic compound of the whole series, could be due to larger number of intermolecular interactions and to the best position of the naphthalimido rings, which favours pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Moreover, 12 was designed as a DNA topoisomerase II poison and biochemical studies showed its effect on human DNA topoisomerase II. We then selected the compounds with a significant cytotoxicity for apoptosis assay. Derivative 9 was able to induce significantly apoptosis (40%) at 0.1 microM concentration, and we demonstrated that the effect on apoptosis in HT-29 cells is mediated by caspases activation.
authors.affiliation: Department of Pharmaceutical Science, University of Salerno, via Ponte Don Melillo, variante 11C, 84084 Fisciano, Italy. rfilosa@unisa.it
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.forename: Simone Di
authors.initials: SD
authors.lastname: Micco
authors.forename: Paolo de
authors.initials: Pd
authors.lastname: Caprariis
authors.forename: Michela
authors.initials: M
authors.lastname: Festa
authors.forename: Antonello
authors.initials: A
authors.lastname: Petrella
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capranico
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006801:Humans; D008958:Models, Molecular; D053644:Naphthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D053644:Naphthalimides; D059005:Topoisomerase II Inhibitors