Scaffold optimization of indeno[2,1-g]pteridine sulfonates for enhanced DNA interactions, ROS generation, and Topo II...

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Drug Discovery

Background:

• Pteridine derivatives exhibit DNA-binding affinity.
• Sulfonate moieties possess covalent crosslinking abilities.
• Developing novel DNA-damaging agents is crucial for cancer therapy.

Purpose of the Study:

• Design and synthesize novel indeno[2,1-g]pteridine sulfonate derivatives.
• Evaluate their potential as multi-modal DNA-damaging agents.
• Investigate their antiproliferative activities and mechanisms of action.

Main Methods:

• Chemical synthesis and scaffold optimization.
• In vitro antiproliferative assays against A549 and HeLa cell lines.
• DNA interaction studies, ROS level measurements, molecular docking, and molecular dynamics simulations.
• Electrochemical studies for metabolic pathway exploration.

Main Results:

• Compounds 8q and 8r demonstrated significant antiproliferative activity.
• These compounds induce multi-modal DNA damage, including oxidative stress.
• Molecular docking and dynamics simulations confirmed strong binding affinity to DNA and DNA Topoisomerase II (Topo II).
• Inhibition of Topo II by 8q and 8r was comparable to mitonafide.
• Extended metabolic elimination times were observed for 8q and 8r compared to busulfan.

Conclusions:

• Novel indeno[2,1-g]pteridine sulfonates are effective DNA-damaging agents with significant antiproliferative potential.
• Compounds 8q and 8r exhibit promising anti-cancer properties through multi-modal DNA damage and Topo II inhibition.
• Their favorable pharmacokinetic profiles suggest potential for improved drug delivery and reduced dosing frequency.