Novel 1H-imidazo[4,5-c]quinoline derivatives as TLR-7 modulators with pro-apoptotic properties in breast cancer cell...

A new class of 4-chloro-substituted 1H-imidazo[4,5-c]quinoline derivatives was identified as functional TLR7 agonists. Molecular modeling suggests that, in selected cases, replacing the C4 amino group with chlorine does not abolish receptor activation, since the chlorine substituent can participate in halogen bonding within the binding site. Systematic structural modifications within this series led to the discovery of compound 14, which demonstrated both robust TLR7 agonist activity and marked cytotoxic effects against the MCF-7 breast cancer cell line. Compound 14 exhibited a favorable selectivity profile, showing minimal activity toward other cancer cell lines, low toxicity in fibroblasts, and promising metabolic stability. Further investigations indicated that its cytotoxicity is mediated through activation of the intrinsic apoptotic pathway, driven by ROS production and caspase activation. Notably, within this compounds set, cytotoxic activity of 14 did not show a clear dependence on TLR7 agonist activity. These findings expand the structure-activity understanding of imidazoquinoline-based modulators and identify chloro-substituted derivatives, particularly compound 14, as promising candidates for further development.