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 4. Biological test results showed that the new compounds are good to outstanding NAALADase inhibitors. Compounds 8b and 10b showed activity similar to the known potent inhibitor (S)-2-PMPA. Fluorescently labeled inhibitor 19b may potentially be used to study binding to prostate cancer cells by fluorescence microscopy, and siderophore-containing inhibitor 21b may be useful for detection of prostate-derived cancer cells by magnetic resonance imaging (MRI).