Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer

► The FDA-approved drug, methylene blue (MB), was identified by high-throughput screening as a promising scaffold for binding the c-myc oncogene G-quadruplex DNA. ► Addition of side chains improved the inhibiting activity of the derivatives compared to the parent compound. ► The most potent MB derivative investigated could induce or stabilize c-myc G-quadruplex formation in both cell-free and cellular biological models, and display higher cytotoxicity against human hepatocarcinoma cells compared to parent compound, MB.