Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic targets.
• Overexpression of the c-MYC oncogene is implicated in TNBC progression.
• Current c-MYC inhibitors targeting G-quadruplex structures have shown limited clinical success.

Purpose of the Study:

• To design and synthesize novel acridone derivatives as potential c-MYC G-quadruplex stabilizers.
• To evaluate the anti-cancer activity and selectivity of these derivatives against TNBC cells.
• To investigate the mechanism of action, including the role of intracellular reactive oxygen species (ROS).

Main Methods:

• Synthesis of 29 acridone derivatives.
• Assessment of intracellular ROS levels and cell viability.
• Quantitative Structure-Activity Relationship (QSAR) analysis.
• Molecular docking studies.
• Evaluation of anti-tumor activity in a TNBC cell line.

Main Results:

• Acridone derivatives were synthesized and screened for anti-cancer properties.
• Compound N8 significantly increased intracellular ROS levels in TNBC cells.
• N8 demonstrated potent anti-tumor activity and high selectivity.
• QSAR and molecular docking supported the potential of acridone derivatives to stabilize c-MYC G-quadruplex structures.

Conclusions:

• Acridone derivatives show promise as novel therapeutic agents for TNBC.
• Compound N8 is a lead candidate warranting further investigation due to its potent and selective anti-tumor effects.
• Stabilization of the c-MYC G-quadruplex structure is a viable strategy for TNBC treatment.