Molecular-docking-guided design, synthesis, and biologic evaluation of radioiodinated quinazolinone prodrugs

Area of Science:

• Biomedical Engineering
• Radiochemistry
• Oncology

Background:

• Enzyme-mediated cancer imaging and therapy (EMCIT) utilizes in vivo precipitation of radioactive molecules.
• Extracellular enzymes overexpressed by cancer cells trigger this precipitation.
• Targeted cancer visualization and treatment remain critical challenges.

Purpose of the Study:

• To model and assess novel iodinated quinazolinone derivatives for EMCIT.
• To evaluate their interaction with human placental alkaline phosphatase (PLAP).
• To synthesize and characterize the most promising derivative for in vivo application.

Main Methods:

• Molecular modeling using AutoDock 3.0 to predict binding affinities.
• Synthesis and characterization of ammonium 2-(2',4'-diphosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ2-P,4-P).
• In vitro enzymatic conversion assays and in vivo biodistribution studies in mice.

Main Results:

• IQ2-P,4-P demonstrated favorable calculated inhibition constants with PLAP.
• PLAP-mediated conversion yielded water-insoluble precipitates.
• Autoradiography confirmed hydrolysis by cancer cells and extracellular precipitation.
• Biodistribution studies showed minimal retention in normal tissues.

Conclusions:

• The developed iodinated quinazolinone derivative is effective for EMCIT.
• The study validates the potential of the EMCIT approach for cancer diagnostics and therapeutics.
• Further research into this class of compounds is warranted.