Synthesis and in Vitro Evaluation of Novel 5‐Nitroindole Derivatives as c‐Myc G‐Quadruplex Binders with Anticancer Activity

Lead‐optimization strategies for compounds targeting c‐Myc G‐quadruplex (G4) DNA are being pursued to develop anticancer drugs. Here, we investigate the structure‐activity‐ relationship (SAR) of a newly synthesized series of molecules based on the pyrrolidine‐substituted 5‐nitro indole scaffold to target G4 DNA. Our synthesized series allows modulation of flexible elements with a structurally preserved scaffold. Biological and biophysical analyses illustrate that substituted 5‐nitroindole scaffolds bind to the c‐Myc promoter G‐quadruplex. These compounds downregulate c‐Myc expression and induce cell‐cycle arrest in the sub‐G1/G1 phase in cancer cells. They further increase the concentration of intracellular reactive oxygen species. NMR spectra show that three of the newly synthesized compounds interact with the terminal G‐quartets (5′‐ and 3′‐ends) in a 2 : 1 stoichiometry.