Design and synthesis of novel styrylquinolinium derivatives for the treatment of breast Cancer: Targeting the c-Myc G-quadruplex

Inhibiting c-Myc gene expression by targeting the c-Myc G-quadruplex (G4) represents an effective strategy for breast cancer treatment. In order to find ligands that can specifically target the c-Myc G4, we utilized styrylquinolinium as the core element to anchor G4, and proposed three guiding principles for the design and synthesis of G4 ligands. Finally, compound W11 was identified as the compound skeleton which has the potential to target c-Myc G4. On this basis, compound X3 with higher c-Myc G4 selectivity was developed. Both W11 and X3 demonstrate significant inhibitory effects on breast cancer. Subsequently, we used molecular docking and molecular dynamics simulation to analyze the relationship between the targeting ability and chemical structure of W11 derivatives, and proposed a detailed structure-activity relationship model. Additionally, we found that the free energy landscape (FEL) of ligands with high selectivity and affinity for G4 is "centralized and singular" during this process. Cell experiments and MCF-7 tumor xenograft experiments demonstrated that W11 inhibited the proliferation and metastasis of breast cancer cells by downregulating the transcription and translation of the c-Myc gene. Moreover W11 significantly inhibited tumor tissue growth in vivo without causing obvious damage to major organs.