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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Triple-negative breast cancer (TNBC) lacks effective clinical treatments.
• The c-myc oncogene plays a crucial role in TNBC development.
• G-rich sequences in the c-myc promoter can form G-quadruplex structures, offering a therapeutic target.

Purpose of the Study:

• To synthesize and investigate chiral ruthenium(II) complexes for their ability to interact with c-myc G-quadruplex DNA.
• To evaluate the anti-cancer efficacy of these complexes against TNBC cells.
• To elucidate the mechanism of action for promising compounds.

Main Methods:

• Synthesis of chiral ruthenium(II) complexes ([Ru(bpy)2(DPPZ-R)](ClO4)2).
• Assessment of DNA binding affinity and stability with c-myc G-quadruplex DNA.
• In vitro cytotoxicity assays against various tumor cell lines, including MDA-MB-231.
• In vivo evaluation in a zebrafish xenograft breast cancer model.
• Mechanistic studies involving DNA damage and apoptosis induction.

Main Results:

• Ruthenium(II) complex 3 (containing an alkinyl group) demonstrated high affinity and stability for c-myc G-quadruplex DNA.
• Complex 3 exhibited significant inhibition against tumor cells, comparable to cisplatin.
• Complex 3 showed cytotoxic activity in a zebrafish TNBC model.
• The compound primarily induces cell death through DNA-damage-mediated apoptosis.

Conclusions:

• Ruthenium(II) complexes with alkinyl substituents are effective c-myc G-quadruplex DNA binders.
• These complexes represent a potential therapeutic strategy for blocking TNBC progression.
• Further development of these Ru(II) complexes could lead to novel TNBC treatments.