Journal article
N-Substituted Glutamyl Sulfonamides As Inhibitors Of Glutamate Carboxypeptidase II (GCP2)
Chemical biology & drug design, Vol.77(4), pp.241-247
04/2011
Handle:
https://hdl.handle.net/2376/105602
PMCID: PMC3055939
PMID: 21219587
Abstract
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 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 (phophonates and phosphoramidates) is tetrahedral and negatively charged at neutral pH, while glutamyl urea class of inhibitors possess 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.
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Details
- Title
- N-Substituted Glutamyl Sulfonamides As Inhibitors Of Glutamate Carboxypeptidase II (GCP2)
- Creators
- Brian R Blank - Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132Pinar Alayoglu - Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132William Engen - Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132Joseph K Choi - Department of Chemistry, Washington State University, Pullman, WA 99164Clifford E Berkman - Department of Chemistry, Washington State University, Pullman, WA 99164Marc O Anderson - Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132
- Publication Details
- Chemical biology & drug design, Vol.77(4), pp.241-247
- Academic Unit
- Chemistry, Department of
- Identifiers
- 99900546832601842
- Language
- English
- Resource Type
- Journal article