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 ((125) IQ(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 (125) IQ(2-S) and (125) IQ(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-[(125) I]iodo-4-(3H)-quinazolinone ((125) IQ(2-OH)). The in vitro incubation of (127) IQ(2-S) and (127) IQ(2-P) with pancreatic, ovarian, and prostate cancer cells expressing studied hydrolases also results in their hydrolysis and the precipitation of (127) IQ(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 ((123) I/(124) I/(131) I) and radiotherapy ((131) I) of pancreatic cancer.
Harvard Medical School, Department of Radiology, 200 Longwood Avenue, Boston, MA 02115, USA. pavel.pospisil@gmail.com
Pavel
P
Pospisil
Houari
H
Korideck
Ketai
K
Wang
Yongliang
Y
Yang
Lakshmanan K
LK
Iyer
Amin I
AI
Kassis
D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D003198:Computer Simulation; D006801:Humans; D006868:Hydrolysis; D007457:Iodine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology; D015238:Sulfotransferases / Q000737:chemistry / Q000378:metabolism
D007457:Iodine Radioisotopes; D011355:Prodrugs; D052999:Quinazolinones; C470791:SULF1 protein, human; D015238:Sulfotransferases