Novel Chiral Ru(II) Complexes as Potential c-myc G-quadruplex DNA Stabilizers Inducing DNA Damage to Suppress Triple-Negative Breast Cancer Progression.

Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy to fight cancer. Herein, a series of chiral ruthenium(II) complexes ([Ru(bpy)(DPPZ-R)](ClO), -1: R = -H, -2: R = -Br, -3: R = -C≡C(CH)NH) were researched based on their interaction with c-myc G-quadruplex DNA. - and - show high affinity and stability to decrease their replication. Additional studies showed that - and - exhibit higher inhibition against different tumor cells than other molecules. - decreases the viability of MDA-MB-231 cells with an IC of 25.51 μM, which is comparable with that of cisplatin, with an IC of 25.9 μM. Moreover, - exhibits acceptable cytotoxic activity against MDA-MB-231 cells in a zebrafish xenograft breast cancer model. Further studies suggested that - decreases the viability of MDA-MB-231 cells predominantly through DNA-damage-mediated apoptosis, which may be because - can induce DNA damage. In summary, the results indicate that Ru(II) complexes containing alkinyl groups can be developed as c-myc G-quadruplex DNA binders to block TNBC progression.