Glutamate carboxypeptidase II (GCP2) is a membrane-bound cell-surface
peptidase which is implicated in several
neurological disorders and is also over-expressed in prostate
tumor cells. There is a significant interest in the inhibition of GCP2 as a means of neuroprotection, while GCP2 inhibition as a method to treat
prostate cancer remains a topic of further investigation. The key
zinc-binding functional group of the well-characterized classes of GCP2 inhibitors (
phosphonates and phosphoramidates) is tetrahedral and negatively charged at neutral pH, while glutamyl
urea class of inhibitors possesses a planar and neutral
zinc-binding group. This study introduces a new class of GCP2 inhibitors, N-substituted glutamyl
sulfonamides, which possess a neutral tetrahedral
zinc-binding motif. A library containing 15 secondary
sulfonamides and 4 tertiary (N-methyl)
sulfonamides was prepared and evaluated for inhibitory potency against purified GCP2
enzyme activity. While most inhibitors lacked potency at 100 μm, short alkyl
sulfonamides exhibited promising low micromolar potency, with the optimal inhibitor in this series being glutamyl N-(propylsulfonamide) (2g). Lastly, molecular docking was used to develop a model to formulate an explanation for the relative inhibitory potencies employed for this class of inhibitors.