Molecular-docking-guided design, synthesis, and biologic evaluation of radioiodinated quinazolinone prodrugs.
Enzyme-mediated cancer imaging and therapy (EMCIT) is a novel approach in which radioactive water-soluble molecules are precipitated in vivo following their hydrolysis by extracellular enzymes overexpressed by cancer cells. AutoDock 3.0 was used to model the interaction-binding between a series of iodinated quinazolinone derivatives and human placental alkaline phosphatase (PLAP, crystal structure in the Protein Data Bank) and to assess the effects of structural modification of the derivatives. Ammonium 2-(2',4'-diphosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ2-P,4-P), having the most favorable calculated inhibition constant, was synthesized and characterized. Concentration-dependent, PLAP-mediated conversion of IQ2-P,4-P (4)/125IQ2-P,4-P (6) to water-insoluble 2-(2',4'-dihydroxyphenyl)-6-[127I/125I]iodo-4-(3H)-quinazolinone (127IQ2-OH,4-OH (2)/125IQ2-OH,4-OH (7)) was observed in solution. Autoradiography indicated that 6 is hydrolyzed by human cancer cells and the resulting 7 precipitates on exterior cell surfaces. Biodistribution studies in mice demonstrated that 6 is minimally retained by normal tissues. The findings support the validity of the EMCIT approach.
Chen
Kai
K
Department of Radiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Aowad
Ayman F Al
AF
Adelstein
S James
SJ
Kassis
Amin I
AI
D000469:Alkaline Phosphatase / Q000737:chemistry; D000818:Animals; D001345:Autoradiography; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D007456:Iodine Isotopes; D007457:Iodine Radioisotopes; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D012996:Solutions; D014018:Tissue Distribution
D007456:Iodine Isotopes; D007457:Iodine Radioisotopes; D008024:Ligands; D011355:Prodrugs; D052999:Quinazolinones; D012996:Solutions; D000469:Alkaline Phosphatase