Exploiting the 5-amino-11H-indolo[3,2-c]isoquinoline Core to Achieve Better G-quadruplex Ligands for Cancer Therapy.

Abstract

G-quadruplexes (G4) are secondary structures that can form within guanine-rich  nucleic acids 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. In this study, we report the synthesis of mono- and di-substituted 5-amino-11H-indolo[3,2-c]isoquinolines. Fluorescence spectroscopy studies indicate that substitution in position 11 dictates the preference of binding to different G4. Compound 10, which features a ethylpyrrolidine side chain, demonstrated a binding preference by one order of magnitude for parallel c-MYCG4 (Kb = 107 M-1), over parallel k-RASG4 (Kb = 106 M-1), hybrid TeloG4 and dsDNA (Kb = 105 M-1). Molecular docking studies revealed that compound 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, compound 10 drastically reduced the cell viability of breast cancer cells at a concentration of 10 µM. Overall, herein we report the discovery of a new potent and selective G4 ligand, with reduced number of side chains and antiproliferative activity in cancer cells that deserves to be further investigated.