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Synthesis and Activity of Analogues of the Isoleucyl tRNA Synthetase Inhibitor SB-203207

Crasto, Curtis; Forrest, Andrew; Karoli, Tomislav; March, Darren; Mensah, Lucy; O'Hanlon, Peter; Nairn, Michael; Oldham, Mark; Yue, Weimin; Banwell, Martin; Easton, Christopher

Description

Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the...[Show more]

dc.contributor.authorCrasto, Curtis
dc.contributor.authorForrest, Andrew
dc.contributor.authorKaroli, Tomislav
dc.contributor.authorMarch, Darren
dc.contributor.authorMensah, Lucy
dc.contributor.authorO'Hanlon, Peter
dc.contributor.authorNairn, Michael
dc.contributor.authorOldham, Mark
dc.contributor.authorYue, Weimin
dc.contributor.authorBanwell, Martin
dc.contributor.authorEaston, Christopher
dc.date.accessioned2015-12-13T23:13:55Z
dc.date.available2015-12-13T23:13:55Z
dc.identifier.issn0968-0896
dc.identifier.urihttp://hdl.handle.net/1885/88353
dc.description.abstractTwenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
dc.publisherPergamon-Elsevier Ltd
dc.sourceBioorganic and Medicinal Chemistry
dc.subjectKeywords: 7 [3 [(2 amino 3 methyl 1 oxopentyl)amino]propanoyl] 2,4a,5,6,7,7a hexahydro 2 methyl 1h cyclopenta[c]pyridine 4 carboxamide; 7 [4 [(2 amino 3 methyl 1 oxopentyl)amino]butanoyl] 2,4a,5,6,7,7a hexahydro 2 methyl 1h cyclopenta[c]pyridine 4 carboxamide; 7 [[
dc.titleSynthesis and Activity of Analogues of the Isoleucyl tRNA Synthetase Inhibitor SB-203207
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume11
dc.date.issued2003
local.identifier.absfor030499 - Medicinal and Biomolecular Chemistry not elsewhere classified
local.identifier.ariespublicationMigratedxPub18023
local.type.statusPublished Version
local.contributor.affiliationCrasto, Curtis, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationForrest, Andrew, GlaxoSmithKline
local.contributor.affiliationKaroli, Tomislav, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationMarch, Darren, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationMensah, Lucy, GlaxoSmithKline
local.contributor.affiliationO'Hanlon, Peter, GlaxoSmithKline
local.contributor.affiliationNairn, Michael, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationOldham, Mark, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationYue, Weimin, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationBanwell, Martin, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationEaston, Christopher, College of Physical and Mathematical Sciences, ANU
local.bibliographicCitation.issue13
local.bibliographicCitation.startpage2687
local.bibliographicCitation.lastpage2694
local.identifier.doi10.1016/S0968-0896(03)00237-2
dc.date.updated2015-12-12T08:36:16Z
local.identifier.scopusID2-s2.0-12444295104
CollectionsANU Research Publications

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