Computational and Biological Evaluation of Quinazolinone Prodrug for Targeting Pancreatic Cancer

Our concept of enzyme‐mediated cancer imaging and therapy aims to use radiolabeled compounds to target hydrolases over‐expressed on the extracellular surface of solid tumors. A data mining approach identified extracellular sulfatase 1 (SULF1) as an enzyme expressed on the surface of pancreatic cancer cells. We designed, synthesized, and characterized 2‐(2′‐sulfooxyphenyl)‐6‐iodo‐4‐(3H)‐quinazolinone (IQ_2‐S) as well as its radioiodinated form (¹²⁵IQ_2‐S) as a prodrug with potential for hydrolysis by SULF1. IQ_2‐S was successfully docked in silico into three enzymes – homolog of SULF1, alkaline phosphatase, and prostatic acid phosphatase. The incubation of ¹²⁵IQ_2‐S and ¹²⁵IQ_2‐P with the three enzymes in solution confirms the docking results and enzyme selectivity for the analogs. The hydrolysis of both radioactive compounds produces the water‐insoluble, fluorescent product 2‐(2′‐hydroxyphenyl)‐6‐[¹²⁵I]iodo‐4‐(3H)‐quinazolinone (¹²⁵IQ_2‐OH). The in vitro incubation of ¹²⁷IQ_2‐S and ¹²⁷IQ_2‐P with pancreatic, ovarian, and prostate cancer cells expressing studied hydrolases also results in their hydrolysis and the precipitation of ¹²⁷IQ_2‐OH fluorescent crystals on the cell surface. To our knowledge, these findings are the first to report the targeting of a radioactive substrate to SULF1 and that this prodrug may be potentially useful in the imaging (¹²³I/¹²⁴I/¹³¹I) and radiotherapy (¹³¹I) of pancreatic cancer.

We identified extracellular sulfatase 1 as an enzyme that is appropriate for our concept of Enzyme‐Mediated Cancer Imaging and Therapy, which aims to use radiolabeled compounds to target hydrolases over‐expressed on the extracellular surface of pancreatic tumor cells. Fluorescent products of the hydrolysis of the newly designed and synthesized sulfurylated quinazolinone derivative suggest its potential for use in imaging and radiotherapeutic treatment of pancreatic cancer.