Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor

Area of Science:

• Medicinal Chemistry
• Nanotechnology
• Molecular Biology

Background:

• Small molecules are crucial for modulating cellular functions.
• Target Guided Synthesis (TGS) identifies potent small molecules for biological targets.
• DNA structures can serve as scaffolds for chemical reactions.

Purpose of the Study:

• To demonstrate an innovative TGS approach using DNA nano-templates.
• To synthesize regioselective triazole products via Huisgen cycloaddition.
• To evaluate the potential of DNA nano-templates in drug discovery.

Main Methods:

• Preparation of G-quadruplex and duplex DNA nano-templates on gold-coated magnetic nanoparticles.
• Facilitation of Huisgen cycloaddition using DNA nano-templates.
• Isolation of triazole products by magnetic decantation.
• Reuse of the G-quadruplex nano-template for multiple reaction cycles.

Main Results:

• Regioselective formation of 1,4-substituted triazole products.
• Successful recovery and reuse of the G-quadruplex nano-template for five cycles.
• The major triazole product inhibits c-MYC expression by targeting the c-MYC promoter G-quadruplex.

Conclusions:

• The nano-TGS approach is effective for synthesizing target-selective small molecules.
• DNA nano-templates offer a reusable and efficient platform for chemical synthesis.
• This strategy holds promise for generating novel ligands in drug discovery.