Controlling anticancer drug mediated G-quadruplex formation and stabilization by a molecular container

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Structural Biology

Background:

• G-quadruplex DNA (GQ-DNA) structures are crucial in biological processes like replication and transcription.
• Controlling GQ-DNA formation and stability by small molecules is vital for therapeutic applications.
• Topotecan (TPT) is an established drug with potential anticancer properties.

Purpose of the Study:

• To investigate the ability of topotecan (TPT) to induce and stabilize G-quadruplex DNA (GQ-DNA) formation.
• To explore the mechanism of TPT binding to GQ-DNA.
• To demonstrate the reversal of TPT-induced GQ-DNA formation using a molecular container, cucurbit[7]uril (CB7).

Main Methods:

• Circular dichroism (CD) spectroscopy
• Fluorescence spectroscopy
• Nuclear Magnetic Resonance (NMR) spectroscopy
• UV melting experiments
• Molecular Dynamics (MD) simulations

Main Results:

• TPT successfully induced and stabilized GQ-DNA formation in the absence of specific ions (Na+/K+).
• TPT primarily binds to the terminal regions of GQ-DNA through stacking interactions.
• Cucurbit[7]uril (CB7) effectively reverted the GQ-DNA conformation to its original state by sequestering TPT.

Conclusions:

• TPT is an effective inducer and stabilizer of GQ-DNA structures.
• The TPT-GQ-DNA interaction is reversible using the molecular container CB7.
• Fluorescence color switching of TPT provides a simple method for detecting these conformational transitions.