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  = 10 7   m −1 ), over parallel k‐RASG4 ( K b  = 10 6   m −1 ), and hybrid TeloG4 and dsDNA ( K b  = 10 5   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 μ m . 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.