Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands

Simple item page
dc.contributor.authorInglis, S.
dc.contributor.authorJones, R.
dc.contributor.authorFritz, D.
dc.contributor.authorStojkoski, C.
dc.contributor.authorBooker, G.
dc.contributor.authorPyke, S.
dc.date.issued2005
dc.description.abstractThe Src homology 3 (SH3) domains are small protein–protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines as ligands for SH3 domains—so far the only reported examples of entirely small-molecule ligands for the SH3 domains. The highest affinity 2-aminoquinolines so far identified are 6-substituted compounds. In this article, the synthesis of several new 2-aminoquinolines, including 5-, 6- and 7-substituted compounds, for Tec SH3 domain ligand binding studies is presented. As a part of the synthetic investigation, the utility of different methods for the synthesis of 2-aminoquinolines was explored and potentially powerful methods were identified for the synthesis of 2-aminoquinolines with diverse functionality. Of the compounds prepared, the 5-substituted-2-aminoquinolines generally bound with similar affinities to unsubstituted 2-aminoquinoline, whilst the 7-substituted compounds generally bound with similar or lower affinity than unsubstituted 2-aminoquinoline. However, the 6-substituted-2-aminoquinolines generally bound with significantly higher affinity than unsubstituted 2-aminoquinoline. In addition, one 6-substituted-N-benzylated-2-aminoquinoline was also tested for SH3 binding and some evidence for the formation of additional contacts at other regions of the SH3 domain was found. These results provide new and useful SAR information that should greatly assist with the challenge of developing high affinity small-molecule ligands for the SH3 domains.
dc.description.statementofresponsibilitySteven Inglis, Rhiannon Jones, Daniel Fritz, Cvetan Stojkoski, Grant Booker and Simon Pyke
dc.identifier.citationOrganic and Biomolecular Chemistry, 2005; 3(14):2543-2557
dc.identifier.doi10.1039/b504498g
dc.identifier.issn1477-0520
dc.identifier.issn1477-0539
dc.identifier.orcidBooker, G. [0000-0001-7207-4699]
dc.identifier.orcidPyke, S. [0000-0002-0061-5115]
dc.identifier.urihttp://hdl.handle.net/2440/17796
dc.language.isoen
dc.publisherRoyal Soc Chemistry
dc.source.urihttps://doi.org/10.1039/b504498g
dc.subjectAminoquinolines
dc.subjectLigands
dc.subjectBinding Sites
dc.subjectMolecular Structure
dc.subjectsrc Homology Domains
dc.subjectModels, Biological
dc.subjectProtein-Tyrosine Kinases
dc.titleSynthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Chemistry publications