title: Tacrine derivatives as dual topoisomerase I and II catalytic inhibitors.
abstract: This study examines the binding properties of a series of newly synthetized tacrine derivatives 1-4 and their anticancer effects. Spectroscopic techniques (UV-Vis, fluorescence spectroscopy, thermal denaturation, and linear spectropolarimetry) and viscometry were used to study DNA binding properties and to determine the types of DNA interaction with the studied derivatives. The binding constants for the complexes with DNA were obtained using UV-Vis spectroscopic titrations (K = 1.6 × 10(4)-4.0 × 10(5) M(-1)) and electrophoretic methods were used to determine the effect of the derivatives on topoisomerase I and II activity. Monotacrine derivative 1 showed evidence of topoisomerase Irelaxation activity at a concentration of 30 × 10(-6) M, while bistacrine derivatives 2-4 produced a complete inhibition of topoisomerase Iat a concentration of 5 × 10(-6) M. The biological activities of the derivatives were studied using MTT-assay and flow cytometric methods (detection of mitochondrial membrane potential and measurement of cell viability) following incubation of 24 and 48 h with human leukemic cancer cell line HL60. The ability of the derivatives to impair cell proliferation was also tested through the analysis of cell cycle distribution.
authors.affiliation: Department of Biochemistry, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janočková
authors.affiliation: Department of Biochemistry, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Plšíková
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Koval'
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Jendželovský
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Jaromír
authors.initials: J
authors.lastname: Mikeš
authors.affiliation: Institute of Biophysics, Department of Molecular Biophysics and Pharmacology, Academy of Science of the Czech Republic, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kašpárková
authors.affiliation: Institute of Biophysics, Department of Molecular Biophysics and Pharmacology, Academy of Science of the Czech Republic, Brno, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Slávka
authors.initials: S
authors.lastname: Hamuľaková
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Fedoročko
authors.affiliation: Department of Biochemistry, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic; Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. Electronic address: maria.kozurkova@upjs.sk.
authors.forename: Mária
authors.initials: M
authors.lastname: Kožurková
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D026942:DNA Topoisomerases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007364:Intercalating Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D013619:Tacrine; D004247:DNA; D026942:DNA Topoisomerases
keywords: Spectroscopic techniques; Tacrine derivatives; Topoisomerase I and II