Cationic side chain-functionalized heteroarene-fused anthraquinones as selective G-quadruplex stabilizers

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• G-quadruplexes (G4s) are crucial nucleic acid structures involved in key cellular processes and are promising anticancer targets.
• Anthraquinone derivatives are effective G4 ligands due to their planar structure, promoting selective binding to G4s over duplex DNA.

Purpose of the Study:

• To synthesize and evaluate novel heterocyclic-fused anthraquinone derivatives as G4 ligands for anticancer therapy.
• To investigate the structure-activity relationships influencing G4 stabilization, selectivity, and antiproliferative effects.

Main Methods:

• Synthesis of indole-, thiazole-, quinoline-, and quinoxaline-fused anthraquinones with cationic side chains.
• FRET-melting and fluorescence assays to assess G4 stabilization and DNA selectivity.
• Antiproliferative assays against leukemia and colon carcinoma cell lines.
• Molecular modeling and confocal fluorescence microscopy for cellular uptake and binding studies.

Main Results:

• Thiazole-fused anthraquinones demonstrated superior stabilization of telomeric and c-Myc G-quadruplexes with high selectivity over duplex and imperfect G4s.
• These compounds exhibited significant antiproliferative activity against K562 and HCT116 cancer cells.
• Molecular modeling confirmed preferential binding of thiazole ligands to G4 DNA, and cellular studies showed efficient uptake and nuclear accumulation.
• Specific compounds (7b and 9b) downregulated c-Myc expression, indicating G4-mediated transcriptional modulation.

Conclusions:

• Heterocyclic core structure is critical for G4 binding affinity and selectivity.
• Thiazole-fused anthraquinones represent a promising class of G4 ligands with potent and selective anticancer activity.
• G4 stabilization and subsequent oncogene downregulation contribute to the observed antiproliferative effects.