Guanidino-Aryl Derivatives: Binding to DNA, RNA and G-Quadruplex Structure and Antimetabolic Activity

A series of novel guanidino-aryl (<b>GA</b>) compounds containing phenanthrene, fluoranthene, fluorene, and naphthalene aromatic cores were synthesized to investigate their interactions with DNA, RNA, and G-quadruplex structures. Among the novel compounds, the phenanthrene-guanidino compound demonstrated the highest micromolar affinity for AT-DNA, possibly due to partial phenanthrene intercalation in addition to hydrogen bonding and electrostatic interactions of guanidine cation. All new guanidino-aryl <b>GA</b> compounds bind strongly to the Tel22 G-quadruplex structure with similar affinities regardless of aromatic core size. The 1:1 stoichiometric complex is stabilised by π-π stacking interactions with the top or bottom G-tetrad, together with strong electrostatic interactions of the guanidino cation. The guanidino-porphyrin PoGU displayed distinct binding stoichiometry, indicating possible sandwiching between two G-quadruplex structures. Within the <b>GA</b> compounds tested, guanidino-fluorene exhibited moderate antimetabolic activity against the HeLa cell line, without selectivity against the healthy cell line.