Computational and Biological Evaluation of Quinazolinone Prodrug for Targeting Pancreatic Cancer

Abstract

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. © 2012 John Wiley & Sons A/S.