Molecular modelling studies, synthesis and biological activity of a series of novel bisnaphthalimides and their development as new DNA topoisomerase II inhibitors.
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.
Filosa
Rosanna
R
Department of Pharmaceutical Science, University of Salerno, via Ponte Don Melillo, variante 11C, 84084 Fisciano, Italy. rfilosa@unisa.it
Peduto
Antonella
A
Micco
Simone Di
SD
Caprariis
Paolo de
Pd
Festa
Michela
M
Petrella
Antonello
A
Capranico
Giovanni
G
Bifulco
Giuseppe
G
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
D004791:Enzyme Inhibitors; D053644:Naphthalimides; D059005:Topoisomerase II Inhibitors