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dc.contributor.authorSeixas, João D
dc.contributor.authorLuengo-Arratta, Sandra A
dc.contributor.authorDiaz, Rosario
dc.contributor.authorSaldivia, Manuel
dc.contributor.authorRojas-Barros, Domingo I
dc.contributor.authorManzano, Pilar
dc.contributor.authorGonzalez, Silvia
dc.contributor.authorBerlanga, Manuela
dc.contributor.authorSmith, Terry K
dc.contributor.authorNavarro, Miguel
dc.contributor.authorPollastri, Michael P
dc.date.accessioned2014-07-15T16:01:01Z
dc.date.available2014-07-15T16:01:01Z
dc.date.issued2014-06-12
dc.identifier.citationSeixas , J D , Luengo-Arratta , S A , Diaz , R , Saldivia , M , Rojas-Barros , D I , Manzano , P , Gonzalez , S , Berlanga , M , Smith , T K , Navarro , M & Pollastri , M P 2014 , ' Establishment of a structure-activity relationship of the 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness ' , Journal of Medicinal Chemistry , vol. 57 , no. 11 , pp. 4834-4848 . https://doi.org/10.1021/jm500361ren
dc.identifier.issn0022-2623
dc.identifier.otherPURE: 118164378
dc.identifier.otherPURE UUID: 04e9f8a7-f115-4d97-8725-880f3c10ded3
dc.identifier.otherPubMed: 24805946
dc.identifier.otherWOS: 000337336600030
dc.identifier.otherScopus: 84902491235
dc.identifier.urihttp://hdl.handle.net/10023/5019
dc.description.abstractThe compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against T. brucei cultures. With an eye towards using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, improve the physicochemical properties and improve the selectivity profile over human kinases. In this work we have developed structure-activity relationships (SAR) for analogs of 1 and have prepared analogs of 1 with improved solubility properties and good predicted central nervous system exposure. In that way, we have identified 4e, 9, 16e and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases.
dc.format.extent15
dc.language.isoeng
dc.relation.ispartofJournal of Medicinal Chemistryen
dc.rights© 2014 American Chemical Society. This is an article distributed in accordance with the terms of the Creative Commons Attribution (CC BY NC 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for noncommercial use, provided the original work is properly cited.en
dc.subjectAfrican sleeping sicknessen
dc.subjectStructure-activity relationshipen
dc.subjectInhibitorsen
dc.subjectPhosphoinositol-kinaseen
dc.subjectQH301 Biologyen
dc.subject.lccQH301en
dc.titleEstablishment of a structure-activity relationship of the 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sicknessen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1021/jm500361r
dc.description.statusPeer revieweden


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