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Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Title
Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization
Author(s)
Youn, SihyunKim, Kyung ImPtacek, JakubOk, KiwonNovakova, ZoraKim, YunHyeKoo, JaeHyungBarinka, CyrilByun, Youngjoo
Issued Date
2015-11-15
Citation
Bioorganic and Medicinal Chemistry Letters, v.25, no.22, pp.5232 - 5236
Type
Article
Author Keywords
CarboraneGlutamate carboxypeptidase IIX-ray crystal structure
Keywords
ANALOGSAnalogs and DerivativesAntagonists and InhibitorsArticleBORONBoron CompoundsBoron DerivativeCarboraneCarborane DerivativeChemistryControlled StudyCrystal StructureCrystallography, X-RayDERIVATIVESDrug SynthesisEFFICACYEnzyme InhibitorEnzyme InhibitorsFluorescenceGlutamate Carboxypeptidase IIGlutamate Carboxypeptidase II InhibitorHumanHumansHydrogen BondMemBRANE ANTIGEN PSMANEUTRON-CAPTURE THERAPYPHARMACOPHOREPROGESTERONE-RECEPTor ANTAGONISTSPROSTATE-CANCERStructure AnalysisSynthesisUltrastructureUreaX-Ray Crystal StructureX Ray Crystallography
ISSN
0960-894X
Abstract
Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79 Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors. © 2015 Elsevier Ltd. All rights reserved.
URI
http://hdl.handle.net/20.500.11750/2577
DOI
10.1016/j.bmcl.2015.09.062
Publisher
Elsevier Ltd
Related Researcher
  • 구재형 Koo, JaeHyung
  • Research Interests 장내미생물/감염균 유래 대사체를 통한 신경염증; 알츠하이머병; 우울증; 당뇨/비만; 대사체/수용체 상호작용에 의한 대사연구
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Department of New Biology Brain-Immune Axis Laboratory 1. Journal Articles

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