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N‐Substituted Glutamyl Sulfonamides as Inhibitors of Glutamate Carboxypeptidase II (GCP2)
Author(s) -
Blank Brian R.,
Alayoglu Pinar,
Engen William,
Choi Joseph K.,
Berkman Clifford E.,
Anderson Marc O.
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01085.x
Subject(s) - chemistry , enzyme , glutamate carboxypeptidase ii , stereochemistry , potency , docking (animal) , biochemistry , prostate cancer , in vitro , biology , cancer , medicine , nursing , genetics
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 μ m , 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.