Carbohydrate-based heteronuclear complexes as topoisomerase Iα inhibitor: approach toward anticancer...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Materials Science

Background:

• Topoisomerases are crucial enzymes for DNA replication and are key targets in anticancer drug development.
• There is a need for novel metallodrugs that can specifically target DNA and inhibit topoisomerase activity.

Purpose of the Study:

• To synthesize and characterize new metal-based glycoconjugate entities with heterobimetallic cores (CuII-SnIV and NiII-SnIV).
• To investigate the DNA binding, DNA cleavage, topoisomerase I inhibition, and in vitro cytotoxicity of these novel complexes.

Main Methods:

• Synthesis and characterization of CuII-SnIV and NiII-SnIV complexes derived from an N-glycoside ligand.
• Computational studies (DFT calculations) for structural optimization and vibrational analysis.
• In vitro biophysical studies for DNA binding, DNA cleavage assays (pBR322, T4 DNA enzymatic assay), and topoisomerase I inhibition assays.
• In vitro cytotoxicity evaluation against a panel of cancer cell lines and intracellular localization studies using confocal microscopy.

Main Results:

• The study reports the successful synthesis and characterization of two novel heterobimetallic complexes, CuII-SnIV (1) and NiII-SnIV (2).
• Complex 1 demonstrated significant DNA binding affinity and induced pBR322 DNA cleavage through a hydrolytic mechanism.
• Complex 1 effectively inhibited topoisomerase I activity and exhibited remarkable in vitro anticancer activity (GI50 < 10 μg/ml) against various cancer cells.
• Confocal microscopy confirmed the intracellular localization of Complex 1 in HeLa cells.

Conclusions:

• The synthesized CuII-SnIV (1) and NiII-SnIV (2) complexes represent promising candidates for anticancer drug development targeting topoisomerases.
• Complex 1 shows potent DNA interaction, topoisomerase inhibition, and significant cytotoxicity, warranting further investigation for therapeutic applications.