Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation

NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds. [Display omitted] •Quindoline derivatives with fork-shaped chains combated NRASmut melanoma.•Derivatives strongly stabilized NRAS rG4, with most showing ΔTm > 18 °C.•Hit compound 10b stabilized NRAS rG4 and repressed NRAS translation.•10b showed good antitumor activity in the NRASmut melanoma xenograft mouse model.