A Click Chemistry-Based Artificial Metallo-Nuclease

Area of Science:

• Bioinorganic Chemistry
• Medicinal Chemistry
• DNA Damage and Repair

Background:

• Artificial metallo-nucleases (AMNs) are investigated as potential DNA-damaging therapeutic agents.
• The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction offers a versatile route for constructing complex molecular scaffolds.
• Developing targeted DNA-binding and cleaving agents is crucial for advancing cancer chemotherapy.

Purpose of the Study:

• To design and synthesize a novel C3-symmetric ligand, TC-Thio, for creating copper-binding artificial metallo-nucleases.
• To investigate the DNA binding and cleavage activities of the resulting copper complexes.
• To elucidate the mechanism of DNA damage and repair recognition.

Main Methods:

• Synthesis of the TC-Thio ligand using CuAAC reaction between tris(azidomethyl)mesitylene and ethynyl-thiophene.
• Characterization of the ligand and its copper complexes using X-ray crystallography, mass spectrometry, and DFT calculations.
• Assessment of DNA binding and cleavage activity, mechanistic studies involving superoxide and peroxide, and single-molecule imaging in peripheral blood mononuclear cells.

Main Results:

• The TC-Thio ligand successfully formed multinuclear Cu(II) and Cu(I) complexes.
• Cu(II)-TC-Thio demonstrated potent DNA binding and cleavage activity, targeting the minor groove.
• The DNA damage induced by Cu(II)-TC-Thio was comparable to temozolomide and recognized by base excision repair (BER) enzymes.

Conclusions:

• The 1,2,3-triazole linker is effective for building potent Cu-binding AMN scaffolds.
• Cu(II)-TC-Thio represents a promising new class of DNA-damaging agents with therapeutic potential.
• Understanding the DNA damage and repair pathways provides insights for developing novel cancer therapeutics.