Document Detail


Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.
MedLine Citation:
PMID:  19932968     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.
Authors:
Sarjubhai A Patel; Trideep Rajale; Erin O'Brien; David J Burkhart; Jared K Nelson; Brendan Twamley; Alex Blumenfeld; Monika I Szabon-Watola; John M Gerdes; Richard J Bridges; Nicholas R Natale
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-11-10
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  18     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-04-27     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  202-13     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2009 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Transport System y+ / antagonists & inhibitors,  chemistry,  metabolism*
Amino Acids / chemistry,  pharmacology
Binding Sites
Cell Line, Tumor
Cell Membrane Permeability / drug effects*
Crystallography, X-Ray
Glutamic Acid / metabolism
Humans
Hydrazones / chemistry,  pharmacology
Isoxazoles / chemistry*,  pharmacology*
Models, Molecular
Molecular Structure
Protein Binding
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
NS038444/NS/NINDS NIH HHS; NS30570/NS/NINDS NIH HHS; P20 RR015583-105624/RR/NCRR NIH HHS; P20RR015583/RR/NCRR NIH HHS; R01 NS030570/NS/NINDS NIH HHS; R01 NS030570-12/NS/NINDS NIH HHS; R15 NS038444-04/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acid Transport System y+; 0/Amino Acids; 0/Hydrazones; 0/Isoxazoles; 0/SLC7A11 protein, human; 3KX376GY7L/Glutamic Acid
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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