title: Novel trisubstituted acridines as human telomeric quadruplex binding ligands.
abstract: A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO19. These compounds were synthesized by modifying the molecular structure of BRACO19 at positions 3 and 6 with heteroacyclic moieties. All of the derivatives presented in the study exhibited stabilizing effects on the human telomeric DNA quadruplex. UV-vis spectroscopy, circular dichroism, linear dichroism and viscosimetry were used in order to study the nature of the DNA binding in more detail. The results show that all of the novel derivatives were able to fold the single-stranded DNA sequences into antiparallel G-quadruplex structures, with derivative 15 exhibiting the highest stabilizing capability. Cell cycle analysis revealed that a primary trend of the "braco"-like derivatives was to arrest the cells in the S- and G2M-phases of the cell cycle within the first 72h, with derivative 13 and BRACO19 proving particularly effective in suppressing cell proliferation. All studies derivatives were less toxic to human fibroblast cell line in comparison with HT 29 cancer cell line.
authors.affiliation: Department of Organic Chemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Ungvarsky
authors.affiliation: Department of Biochemistry, Moyzesova 11, 04001 Kosice, Slovak Republic; Associated Tissue Bank of Faculty of Medicine, L. Pasteur University Hospital, Trieda SNP 1, 04166 Kosice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Plsikova
authors.affiliation: Department of Organic Chemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Janovec
authors.affiliation: Department of Cellular Biology, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Koval
authors.affiliation: Department of Cellular Biology, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jaromir
authors.initials: J
authors.lastname: Mikes
authors.affiliation: Department of Cellular Biology, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mikesová
authors.affiliation: Associated Tissue Bank of Faculty of Medicine, L. Pasteur University Hospital, Trieda SNP 1, 04166 Kosice, Slovak Republic.
authors.forename: Denisa
authors.initials: D
authors.lastname: Harvanova
authors.affiliation: Department of Cellular Biology, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Fedorocko
authors.affiliation: Department of Organic Chemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Pavol
authors.initials: P
authors.lastname: Kristian
authors.affiliation: Institute of Biophysics, Department of Molecular Biophysics and Pharmacology, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.affiliation: Institute of Biophysics, Department of Molecular Biophysics and Pharmacology, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: Department of Organic Chemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Maria
authors.initials: M
authors.lastname: Vojtickova
authors.affiliation: Department of Biochemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Danica
authors.initials: D
authors.lastname: Sabolova
authors.affiliation: Department of Biochemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Stramova
authors.affiliation: Associated Tissue Bank of Faculty of Medicine, L. Pasteur University Hospital, Trieda SNP 1, 04166 Kosice, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Rosocha
authors.affiliation: Department of Organic Chemistry, Moyzesova 11, 04001 Kosice, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Imrich
authors.affiliation: Department of Biochemistry, Moyzesova 11, 04001 Kosice, Slovak Republic. Electronic address: maria.kozurkova@upjs.sk.
authors.forename: Maria
authors.initials: M
authors.lastname: Kozurkova
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D008024:Ligands; D004247:DNA; C427203:calf thymus DNA; C454064:BRACO-19
keywords: Braco 19 derivatives; Cell proliferation; DNA binding; G-quadruplex structures; Trisubstituted acridines