Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition

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dc.contributor.authorWinfield, Hannah J.
dc.contributor.authorCahill, Michael M.
dc.contributor.authorO'Shea, Kevin D.
dc.contributor.authorPierce, Larry T.
dc.contributor.authorRobert, Thomas
dc.contributor.authorRuchaud, Sandrine
dc.contributor.authorBach, Stéphane
dc.contributor.authorMarchand, Pascal
dc.contributor.authorMcCarthy, Florence O.
dc.contributor.funderIrish Research Council for Science, Engineering and Technologyen
dc.contributor.funderLigue Contre le Canceren
dc.contributor.funderNational Cancer Instituteen
dc.contributor.funderEuropean Cooperation in Science and Technologyen
dc.date.accessioned2018-11-13T16:49:38Z
dc.date.available2018-11-13T16:49:38Z
dc.date.issued2018-07-09
dc.date.updated2018-11-13T16:39:47Z
dc.description.abstractSynthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.en
dc.description.sponsorshipIrish Research Council for Science, Engineering and Technology (Ulysses scheme); National Cancer Institute (NCI screening program for 60-cell line testing); Cancéropôle Grand-Ouest (axis: Natural sea products in cancer treatment); Ligue Contre le Cancer (CD29, 35, 22 and 75); European Cooperation in Science and Technology (COST Action CA15135)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationWinfield, H. J., Cahill, M. M., O'Shea, K. D., Pierce, L. T., Robert, T., Ruchaud, S., Bach, S., Marchand, P. and McCarthy, F. O. (2018) 'Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition', Bioorganic & Medicinal Chemistry, 26(14), pp. 4209-4224. doi: 10.1016/j.bmc.2018.07.012en
dc.identifier.doi10.1016/j.bmc.2018.07.012
dc.identifier.endpage4224en
dc.identifier.issn0968-0896
dc.identifier.journaltitleBioorganic & Medicinal Chemistryen
dc.identifier.startpage4209en
dc.identifier.urihttps://hdl.handle.net/10468/7109
dc.identifier.volume26en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttp://www.sciencedirect.com/science/article/pii/S0968089618308988
dc.rights© 2018 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 licenseen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectBisindolylmaleimideen
dc.subjectKinase screeningen
dc.subjectMaleimide substitutionen
dc.subjectDrug discoveryen
dc.subjectNCI anticancer screenen
dc.titleSynthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibitionen
dc.typeArticle (peer-reviewed)en
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