New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Tyrosyl-DNA-phosphodiesterase 1 (TDP1) plays a critical role in DNA repair pathways.
• TDP1's involvement in repairing topoisomerase 1 poison-induced DNA damage positions it as a therapeutic target for cancer treatment.
• Topotecan, an anticancer drug, relies on TDP1 activity, making TDP1 inhibition a strategy to potentiate its effects.

Purpose of the Study:

• To synthesize novel 5-hydroxycoumarin derivatives incorporating monoterpene moieties.
• To evaluate the inhibitory potential of these synthesized compounds against TDP1.
• To assess the ability of these TDP1 inhibitors to enhance the cytotoxicity of topotecan in cancer cells.

Main Methods:

• Chemical synthesis of 5-hydroxycoumarin-monoterpene conjugates.
• In vitro enzymatic assays to determine TDP1 inhibitory activity (IC50 values).
• Molecular docking simulations to predict ligand binding within the TDP1 catalytic pocket.
• Cytotoxicity assays using cancer (HeLa) and normal (HEK 293A) cell lines in combination with topotecan.

Main Results:

• Most synthesized coumarin-monoterpene conjugates exhibited significant TDP1 inhibitory activity, with IC50 values in the low micromolar to nanomolar range.
• Geraniol derivative 33a emerged as the most potent TDP1 inhibitor, displaying an IC50 of 130 nM.
• Molecular docking studies indicated favorable interactions of the ligands within the TDP1 catalytic pocket.
• The synthesized conjugates, at non-toxic concentrations, potentiated topotecan's cytotoxicity specifically against HeLa cancer cells, but not against HEK 293A cells.

Conclusions:

• A novel series of 5-hydroxycoumarin derivatives functionalized with monoterpenes has been successfully developed as potent TDP1 inhibitors.
• These compounds demonstrate potential as sensitizers to enhance the therapeutic efficacy of topotecan in cancer treatment by targeting TDP1.
• The findings open avenues for developing new combination therapies for cancer leveraging TDP1 inhibition.