title: Interaction of cholinesterase modulators with DNA and their cytotoxic activity.
abstract: This research was focused on a study of the binding properties of a series of cholinesterase reactivators compounds K075 (1), K027 (2) and inhibitors compounds K524, K009 and 7-MEOTA (3-5) with calf thymus DNA. The nature of the interactions between compounds 1-5 and DNA were studied using spectroscopic techniques (UV-vis, fluorescence spectroscopy and circular dichroism). The binding constants for complexes of cholinesterase modulators with DNA were determined from UV-vis spectroscopic titrations (K=0.5 × 10(4)-8.9 × 10(5)M(-1)). The ability of the prepared analogues to relax topoisomerase I was studied with electrophoretic techniques and it was proved that ligands 4 and 5 inhibited this enzyme at a concentration of 30 μM. The biological activity of the novel compounds was assessed through an examination of changes in cell cycle distribution, mitochondrial membrane potential and cellular viability. Inhibitors 3-5 exhibited a cytotoxic effect on HL-60 (human acute promyelocytic leukaemia) cell culture, demonstrated a tendency to affect mitochondrial physiology and viability, and also forced cells to accumulate in the G1/G0-phase of the cell cycle. The cholinesterase reactivators 1 and 2 were found relatively save from the point of view of DNA binding, whereas cholinesterase inhibitors 3-5 resulted as strong DNA binding agents that limit their plausible use.
authors.affiliation: Institute of Chemistry, Department of Biochemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janockova
authors.affiliation: Institute of Chemistry, Department of Biochemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Gulasova
authors.affiliation: Institute of Chemistry, Department of Biochemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Plsikova
authors.affiliation: University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.affiliation: University Hospital, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jaromir
authors.initials: J
authors.lastname: Mikes
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Lubomir
authors.initials: L
authors.lastname: Culka
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Fedorocko
authors.affiliation: Institute of Chemistry, Department of Biochemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 04001 Kosice, Slovak Republic. Electronic address: maria.kozurkova@upjs.sk.
authors.forename: Maria
authors.initials: M
authors.lastname: Kozurkova
mesh_terms: D000818:Animals; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D002802:Cholinesterases / Q000378:metabolism*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D020536:Enzyme Activators / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D013816:Thermodynamics
chemical_list: D002800:Cholinesterase Inhibitors; D020536:Enzyme Activators; D004247:DNA; C427203:calf thymus DNA; D002802:Cholinesterases; D004264:DNA Topoisomerases, Type I
keywords: Cholinesterase modulators; Cytotoxicity; DNA; HL-60; Oximes; Topoisomerase I