Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Chemical Biology

Background:

• The c-MYC oncogene is a key target for cancer therapy.
• G-quadruplex structures in DNA, particularly in the c-MYC promoter, offer potential therapeutic targets.
• Development of selective ligands for G-quadruplexes is crucial for targeted cancer treatment.

Purpose of the Study:

• To design, synthesize, and evaluate triazole-containing prolinamide derivatives as selective ligands for the c-MYC G-quadruplex.
• To investigate the binding affinity, selectivity, and mechanism of action of these novel compounds.
• To assess the potential of these ligands as anti-cancer agents in hepatocellular carcinoma cells.

Main Methods:

• Modular synthesis of prolinamide derivatives via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC).
• Biophysical evaluation using Förster resonance energy transfer (FRET) melting assays and fluorescent intercalator displacement (FID) assays.
• Structural analysis using molecular modeling and atomic force microscopy (AFM).
• In vitro cellular studies using human hepatocellular carcinoma (HepG2) cells.

Main Results:

• Prolinamide trimers demonstrated significant stabilization of G-quadruplex structures over duplex DNA compared to dimers.
• A specific trimer derivative showed high binding affinity and selectivity for the c-MYC G-quadruplex.
• Molecular modeling indicated stacking of the trimer ligand onto the c-MYC G-quadruplex terminal G-quartet.
• AFM revealed the potential of the tris-prolinamide ligand in regulating supramolecular nanoarchitecture assembly.
• In vitro studies showed inhibition of HepG2 cell proliferation and reduced c-MYC expression.

Conclusions:

• Triazole-containing prolinamide derivatives are effective and selective ligands for the c-MYC G-quadruplex.
• These compounds exhibit promising anti-cancer activity by inhibiting cell proliferation and downregulating c-MYC expression.
• The developed ligands hold potential for the development of novel targeted cancer therapies.