Exploiting the 5‐Amino‐11H‐Indolo[3,2‐c]isoquinoline Core to Achieve Better G‐Quadruplex Ligands for Cancer Therapy

G-quadruplexes (G4) are secondary structures that can form within guanine-rich DNA sequences and have cell proliferation regulatory functions. Targeting DNA G4 structures has emerged as a promising anticancer therapy, highlighting the need for new G4 ligands with reduced number of cationic groups to ensure lower toxicity. Herein, the synthesis of mono- and di-substituted 5-amino-11H-indolo[3,2-c]isoquinolines is reported. Fluorescence spectroscopy studies indicate that substitution in position 11 dictates the preference of binding to different G4. Compound 10, which features an ethylpyrrolidine side chain, demonstrates a binding preference by one order of magnitude for parallel c-MYCG4 (K_b = 10⁷ m^-1), over parallel k-RASG4 (K_b = 10⁶ m^-1), and hybrid TeloG4 and dsDNA (K_b = 10⁵ m^-1). Molecular docking studies reveal that 10 can bind not only to the flat G-quartets but also to bridge between two loops of c-MYCG4 through hydrogen bonds, which may explain its capacity to discriminate between G4. Moreover, 10 drastically reduces the cell viability of breast cancer cells at a concentration of 10 μm. Overall, herein, the discovery of a new potent and selective G4 ligand, with reduced number of side chains and with antiproliferative activity in cancer cells, is reported, which deserves to be further investigated.