title: Design, synthesis and pharmacological activity of novel enantiomerically pure phosphonic acid-based NAALADase inhibitors.
abstract: Inhibitors of NAALADase have shown promise for a variety of diseases associated with glutamate excitotoxicity, and could be useful for the diagnosis and therapy of prostate cancer. A series of novel enantiomerically pure 2-(phosphonomethyl)pentanedioic acid (2-PMPA) based NAALADase inhibitors were synthesized. These compounds were prepared from previously reported (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl ester . Biological test results showed that the new compounds are good to outstanding NAALADase inhibitors. Compounds and showed activity similar to the known potent inhibitor (S)-2-PMPA. Fluorescently labeled inhibitor may potentially be used to study binding to prostate cancer cells by fluorescence microscopy, and siderophore-containing inhibitor may be useful for detection of prostate-derived cancer cells by magnetic resonance imaging (MRI).
authors.affiliation: Walther Cancer Research Center and Department of Chemistry & Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, USA.
authors.forename: Pingyu
authors.initials: P
authors.lastname: Ding
authors.forename: Paul
authors.initials: P
authors.lastname: Helquist
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D063065:Organophosphonates; D043425:Glutamate Carboxypeptidase II