Dipeptide inhibitors of the prostate specific membrane antigen (PSMA): A comparison of urea and thiourea derivatives. (15th June 2021)

• Record Type: Journal Article
• Authors: Young, Jennifer D.; Ma, Michelle T.; Eykyn, Thomas R.; Atkinson, R. Andrew; Abbate, Vincenzo; Cilibrizzi, Agostino; Hider, Robert C.; Blower, Philip J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 42(2021)
• Publication Date: 2021-06-15
• Subjects: Glutamate carboxypeptidase II -- GCP(II) -- Prostate-specific membrane antigen -- PSMA -- Prostate cancer -- Zinc(II) metalloenzyme -- Thiourea; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128044
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: GCP II structure from protein data bank 2OOT (https://www.rcsb.org/structure/2OOT ). Abstract: Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA. We hypothesized that substituting the zinc-coordinating urea group for a thiourea group, thus incorporating a sulfur atom, could facilitate stronger binding to zinc(II) within the active site, and thus improve affinity for GCP(II)/PSMA. A structurally analogous urea and thiourea pair (HO-Glu-C(O)-Glu-OH - compound 5 and HO-Glu-C(S)-Glu-OH - compound 6) were synthesized and the inhibitory concentration (IC50 ) of each compound measured with a cell-based assay, allowing us to refute the hypothesis: the thiourea analogue showed 100-fold weaker binding to PSMA than the urea analogue.