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 non-canonical DNA structures involved in vital cellular processes.
• G4s are attractive therapeutic targets, particularly for anticancer drug development.
• Anthraquinone derivatives are effective G4 ligands due to their planar structure facilitating G-tetrad interactions.

Purpose of the Study:

• To synthesize and evaluate novel anthraquinone derivatives fused with heterocyclic systems (indole, thiazole, quinoline, quinoxaline).
• To investigate the structure-activity relationships of these compounds concerning G4 stabilization and selectivity.
• To assess their potential as anticancer agents targeting G4 structures.

Main Methods:

• Synthesis of fused anthraquinone derivatives with cationic side chains.
• FRET-melting and fluorescence assays to determine G4 stabilization and 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 promoter G4s.
• These compounds exhibited high selectivity for G4 DNA over duplex DNA and imperfect G4 structures.
• Significant antiproliferative activity was observed against K562 and HCT116 cancer cells.
• Compounds 7b and 9b effectively downregulated c-Myc oncogene expression.

Conclusions:

• Heterocyclic core structure critically influences G4 binding affinity and selectivity.
• Thiazole-fused anthraquinones represent promising G4 ligands for anticancer therapy.
• G4-mediated transcriptional modulation of oncogenes contributes to the observed antiproliferative effects.