Exploiting the 5-Amino-11H-Indolo[3,2-c]isoquinoline Core to Achieve Better G-Quadruplex Ligands for Cancer Therapy

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• G-quadruplexes (G4) are DNA secondary structures regulating cell proliferation.
• Targeting G4 structures is a promising anticancer strategy.
• Existing G4 ligands often have high toxicity due to multiple cationic groups.

Purpose of the Study:

• To synthesize novel G-quadruplex (G4) ligands with reduced cationic groups for lower toxicity.
• To investigate the binding selectivity and antiproliferative activity of new G4 ligands.
• To discover potent and selective G4 ligands for potential anticancer applications.

Main Methods:

• Synthesis of mono- and di-substituted 5-amino-11H-indolo[3,2-c]isoquinolines.
• Fluorescence spectroscopy to study G4 binding preferences.
• Molecular docking to elucidate binding modes.
• Cell viability assays to assess antiproliferative effects.

Main Results:

• Substitution position 11 dictates G4 binding preference.
• Compound 10 selectively binds parallel c-MYCG4 over other G4 structures and dsDNA.
• Compound 10 exhibits strong antiproliferative activity against breast cancer cells (10 µM).

Conclusions:

• A new class of potent and selective G4 ligands with reduced side chains was discovered.
• Compound 10 demonstrates potential as an anticancer therapeutic agent.
• Further investigation of these novel G4 ligands is warranted.