Chapter 17 - Computational and Biological Evaluation of Radioiodinated Quinazolinone Prodrug for Targeting Pancreatic Cancer

Abstract

The concept of enzyme-mediated cancer imaging and therapy aims to use radiolabeled compounds to target hydrolases overexpressed on the extracellular surface of solid tumors. An approach combining genome and literature data mining was used to identify extracellular sulfatase 1 (SULF1) as an enzyme expressed on the surface of pancreatic cancer cells. Based on our previously studied phosphate-based prodrug 2-(2′-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ2–P), we present its radioiodinated sulfoxyphenylated analog (IQ2–S) as a prodrug with potential for hydrolysis by SULF1. Computational molecular docking approaches were used to dock both analogs into extracellular phosphatases and sulfatases. Prodrug selectivity was simulated in silico and confirmed with the in vitro incubation of these analogs with the enzymes. The hydrolysis of both 125I-labeled compounds produces the water-insoluble products 125IQ2–OH. The in vitro incubation of 127IQ2–S and 127IQ2–P derivatives with T3M4 pancreatic cancer cells, OVCAR-3 ovarian cancer cells, and LNCaP prostate cancer cells resulted in their hydrolysis and the precipitation of 127IQ2–OH fluorescent crystals on the cell surface. These findings were the first to report the targeting of a radioactive substrate to extracellular SULF1 and demonstrate the potential of IQ2–S in imaging (123I/124I/131I) and radiotherapy (131I) of pancreatic cancer.