Premium
Computational and Biological Evaluation of Quinazolinone Prodrug for Targeting Pancreatic Cancer
Author(s) -
Pospisil Pavel,
Korideck Houari,
Wang Ketai,
Yang Yongliang,
Iyer Lakshmanan K.,
Kassis Amin I.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2012.01350.x
Subject(s) - prodrug , pancreatic cancer , chemistry , enzyme , biochemistry , enzymatic hydrolysis , alkaline phosphatase , cancer , medicine
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‐(3 H )‐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‐(3 H )‐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.