Down-Regulation of Oncogene Specifically by Carbazole Derivative Through Opposing Effects on Different Quadruplex Structures of Gene Promoter for Cancer Treatment.

Cancer is one of the leading causes of human mortality worldwide, and aberrant expression of the oncogene is closely associated with the development of numerous malignancies. The promoter region contains G-rich and C-rich sequences capable of forming G-quadruplex (G4) and i-motif (IM or C-quadruplex) structures, respectively. These secondary structures function as "molecular switches" for gene transcriptional regulation and represent promising targets for novel anti-tumor therapeutics. Through extensive screening, we identified carbazole derivative as a unique dual-targeting ligand that simultaneously destabilized the i-motif and stabilized the G-quadruplex, consequently suppressing expression efficiently. In comparison, the single-targeting ligand , which could specifically bind to and unfold the G-quadruplex only, exhibited significantly weaker anti-tumor activity than . Notably, showed potent anti-tumor efficacy in a human colorectal cancer xenograft model without significant toxicity to vital organs. , as a dual-targeting ligand, had specific binding to promoter quadruplexes, with destabilization of the i-motif and concurrent stabilization of the G-quadruplex. This opposing effect could provide a good opportunity for specific gene regulation, with great potential for further development of a precise therapeutic agent. This study provides a novel example for a practical therapeutic approach through coordinated gene quadruplex modulations, which sets up a good foundation for developing high-efficacy anti-tumor drugs without significant side effects.