Novel trisubstituted acridines as human telomeric quadruplex binding ligands

Časopis: BIOORGANIC CHEMISTRY 57, 13-29

Autoři: Ungvarsky, J., Plsikova, J., Janovec, L., Koval, J., Mikes, J., Mikesova, L., Harvanova, D., Fedorocko, P., Kristian, P., Kasparkova, J., Brabec, V., Vojtickova, M., Sabolova, D., Stramova, Z., Rosocha, J., Imrich, J., Kozurkova, M.

Rok: 2014

Abstrakt

A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO-19. 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 Sand G(2)M-phases of the cell cycle within the first 72 h, 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. (C) 2014 Elsevier Inc. All rights reserved.