title: Cytotoxic 3,6-bis((imidazolidinone)imino)acridines: synthesis, DNA binding and molecular modeling.
abstract: New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a-6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA-binding of 6a-6e to ctDNA was examined by UV-vis, fluorescence, and CD spectroscopy. The binding constants determined by UV-vis spectroscopy were found in the range 1.9×10(5)-7.1×10(5) M(-1). An electrophoretic separation proved that ligands 6a-6e inhibited topoisomerase I in 40 μM concentration although only those with longer alkyl chains were able to penetrate the membranes and efficiently suppress the cell proliferation. The highest activity in cytotoxic tests was found for 3,6-bis((1-n-hexyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochloride (6e) with IC(50)=2.12 μM (HL 60) and 5.28 μM (L1210) after 72 h incubation. Molecular dynamics simulations and calculations of solvent-accessible surface areas (SASAs) were used to explore the intercalation mechanism. MD simulations favor stacking between adjacent C:G base pairs from the minor groove side. MD and SASAs calculations indicate that the decrease of K with alkyl extension is due to negative entropic change upon binding.
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, Faculty of Science, Košice, Slovak Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Janovec
authors.forename: Mária
authors.initials: M
authors.lastname: Kožurková
authors.forename: Danica
authors.initials: D
authors.lastname: Sabolová
authors.forename: Ján
authors.initials: J
authors.lastname: Ungvarský
authors.forename: Helena
authors.initials: H
authors.lastname: Paulíková
authors.forename: Jana
authors.initials: J
authors.lastname: Plšíková
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Vantová
authors.forename: Ján
authors.initials: J
authors.lastname: Imrich
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004264:DNA Topoisomerases, Type I / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013816:Thermodynamics
chemical_list: D000166:Acridines; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D004264:DNA Topoisomerases, Type I